Developmental origins of brain disorders: roles for dopamine
Open accessAbstract
Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders.
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Written from the paper’s full text.
TL;DR
This review argues that dopamine acts as a developmental signal—not merely a synaptic neuromodulator—shaping forebrain differentiation and circuit formation before synaptogenesis, with D1- and D2-like receptors often exerting opposing, region-specific effects on proliferation, migration, and dendritic growth. Disruption of these early dopaminergic processes is proposed as a contributor to the pathophysiology of neuropsychiatric disorders such as schizophrenia, autism, ADHD, and substance use disorders.
Key findings
- Dopamine innervation and receptor expression appear early: D3 and D5 receptor mRNA is first found in the striatum at embryonic day (E) 12 and frontal cortex by E15 in mice, and D4 receptor mRNA peaks during embryonic development before declining after birth (with a larger drop in frontal cortex).
- D1- and D2-like receptors have opposing developmental effects: D1-like agonism decreases BrdU incorporation (fewer progenitors dividing) while D1 blockade and D2-like activation increase progenitor division; in migration, D1-like agonism promotes and D2-like agonism decreases cortical GABAergic interneuron migration.
- Receptor effects on neurite outgrowth are region-specific: D1-like agonism reduces neurite outgrowth in frontal cortical cultures but promotes it in striatal cultures (blocked by D1 antagonists), while D2-like activation increases cortical neurite outgrowth and has no effect on striatal neurite outgrowth.
- DA receptor expression peaks in adolescence and then declines; D1 receptor "pruning" in frontal cortex is tied to maturation of excitation-inhibition balance, and adolescent D1 signaling in prefrontal cortex enhances cocaine conditioned place preference (enhanced by D1-like agonist microinjection, blunted by antagonist).
Methods
This is a narrative review; no primary data are reported. It synthesizes rodent and primate/human studies of dopaminergic ontogeny, receptor expression, and genetic/pharmacologic models (e.g., D1 and D2 knockout and overexpression mice, DAT knockout mice, 6-OHDA and mesencephalic lesion models, prenatal cocaine exposure) alongside in vitro primary cortical and striatal culture experiments. It also reviews intracellular signaling evidence (cAMP/PKA, MAPK/ERK, CREB, AKT/GSK3, TrkB interactions) and human genetic association findings (e.g., COMT, DISC-1, DRD2 Taq1 A1 allele, DRD1/DRD2/PPP1R1B, DRD3, DRD4, DAT, AKT1).
Limitations
- Stated: the cellular and functional consequences of developmental DA activity are "still poorly understood," and their linkages to specific diseases are "often indirect and poorly elucidated"; the mechanism for the D1/D2 dichotomy and the signaling pathways mediating subtype-specific effects "remain mostly unknown."
- Stated: genetic association effect sizes "are not large," and the link to DA is "sometimes indirect."
- Evident from the text: much of the mechanistic evidence comes from in vitro culture and rodent models, with the authors noting uncertainty about whether effects are cell-specific (only in the ~10–15% of frontal cortical neurons expressing DA receptors) and whether high agonist concentrations would phenocopy the DAT knockout phenotype (described as "potentially non-physiological"); the authors also note that the effects of reduced or absent D1 signaling on striatal dendritic morphology have not been examined.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
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- Findingown data
Cortical cultures derived from D1 receptor null embryos show increased basal neurite outgrowth compared to cultures from wild-type littermates.
“Our group has also observed increased basal neurite outgrowth in cortical cultures derived from D1 receptor null embryos as compared to cultures derived from wild-type littermates (unpublished data).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Alterations in dopamine-related developmental processes are implicated in the pathophysiology of neuropsychiatric disorders.
“Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders.”
Quote in the paperSubstantial claim - Premisecitation
Alterations in DA innervation patterns and receptor expression have been found in several brain disorders, including psychiatric disease.
“Alterations in DA innervation patterns and receptor expression have been found in several brain disorders, including psychiatric disease.”
Quote in the paperSubstantial claim - Interpretationnone given
Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation.
“Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation.”
Quote in the paperSubstantial claim - Premisecitation
Neurodevelopmental alterations in frontal/prefrontal cortex and striatum are likely involved in the etiology of neuropsychiatric disorders like autism, substance use disorders, and schizophrenia.
“Neurodevelopmental alterations in the frontal/prefrontal cortex and striatum, which are both heavily involved in cognition, memory, emotion, and learning, are likely involved in the etiology of neuropsychiatric disorders like autism, substance use disorders, and schizophrenia (Simpson et al., 2010; Langen et al., 2012; Jonas et al., 2013).”
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- cites Langen et al., 2012
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- cites Jonas et al., 2013
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- Interpretationreasoning
Pharmacologic and genetic disruptions show that developmental effects of dopamine are brain region- and receptor subtype-specific.
“Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific.”
Quote in the paperSubstantial claim - Interpretationreasoning
Dopaminergic signaling has roles beyond neuromodulation at the synapse.
“These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse.”
Quote in the paperSubstantial claim - Premisereasoning
The striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling.
“For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling.”
Quote in the paperSubstantial claim - Interpretationreasoning
The prolonged developmental timeline of the DA system provides a large window of critical periods during which potential disruptors can induce varied effects.
“This prolonged developmental timeline provides a large window of “critical periods” during which potential disruptors can induce varied effects.”
Quote in the paperSubstantial claim - Interpretationnone given
Developmental effects of dopamine, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis.
“These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse.”
Quote in the paperSubstantial claim - Premisecitation
Disruption of genetic and environmental factors in brain development can affect neuronal structure, function, or connectivity and alter developmental trajectory.
“Disruption of these elements can affect neuronal structure, function, or connectivity and can alter developmental trajectory.”
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- cites Lewis and Levitt, 2002
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- Premisecitation
Disruptions of excitation-inhibition balance in the frontal cortex have been reported in patients with schizophrenia, autism, major depressive disorder, and obsessive compulsive disorder.
“Disruptions of excitation-inhibition balance in the frontal cortex have been reported in patients with schizophrenia, autism, major depressive disorder, and obsessive compulsive disorder (Harada et al., 2011; Cornew et al., 2012; Radhu et al., 2013), and many of these patients present with a first episode around adolescence.”
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- Premisenone given
Dopamine receptor expression develops in concert with DAergic innervation.
“Dopamine receptor expression develops in concert with DAergic innervation.”
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Mature DAergic innervation patterns are established in both regions by postnatal day 60.
“Mature DAergic innervation patterns are established in both regions by postnatal day 60.”
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DA innervation develops in well-defined spatiotemporal gradients in the lateral ganglionic eminence that begins by embryonic day 14 and coincides with striatal neurogenesis and cell differentiation.
“Voorn et al. (1988) demonstrated that DA innervation develops in well-defined spatiotemporal gradients in the lateral ganglionic eminence (presumptive striatum) that begins by embryonic day (E) 14 and coincides with striatal neurogenesis and cell differentiation.”
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- Premisecitation
The frontal cortex and striatum are innervated by DA-containing axons from the mesencephalic DA nuclei by mid-to-late gestation in rodents.
“The frontal cortex and striatum are innervated by DA-containing axons from the mesencephalic DA nuclei by mid-to-late gestation in rodents (Verney et al., 1982; Kalsbeek et al., 1988; Voorn et al., 1988), the predominant animal models used to study the developmental roles of DA.”
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Higher levels of expression for both D1 and D2 subtypes are found in the striatum compared to frontal cortex from development to adulthood.
“Higher levels of expression for both subtypes are found in the striatum compared to frontal cortex from development to adulthood (Araki et al., 2007; Sillivan and Konradi, 2011), and the D1 receptor subtype is expressed at higher levels than the D2 receptor subtype in both regions (Boyson et al., 1986; Neisewander et al., 1991; Couppis et al., 2008).”
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Increased D2 receptor binding in the striatum has been observed in patients with ADHD and depression.
“In addition, increased D2 receptor binding in the striatum has been observed in patients with ADHD and depression (D’Haenen and Bossuyt, 1994; Shah et al., 1997).”
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- cites Shah et al., 1997
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Even before DAergic afferents have fully occupied the striatum or cortex, the main two DA receptor subtypes (D1 and D2 receptors) are already present.
“Even before DAergic afferents have fully occupied the striatum or cortex, the main two DA receptor subtypes (D1 and D2 receptors) are already present (Schambra et al., 1994; Araki et al., 2007; Sillivan and Konradi, 2011).”
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D3 receptors are expressed transiently within the early postnatal somatosensory cortex during a key critical period of plasticity.
“D3 receptors are also are expressed transiently within the early postnatal somatosensory cortex during a key critical period of plasticity (Gurevich and Joyce, 2000; Gurevich et al., 2001), although their function there remains unknown.”
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D1 receptor expression steadily declines after the fourth postnatal week.
“Jung and Bennett (1996) demonstrated that D1 receptor expression steadily declines after the fourth postnatal week, which has been confirmed by others and is illustrated in Figure 1C (Andersen et al., 2000; Araki et al., 2007; Brenhouse et al., 2008).”
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The D1 receptor subtype is expressed at higher levels than the D2 receptor subtype in both striatum and frontal cortex.
“Higher levels of expression for both subtypes are found in the striatum compared to frontal cortex from development to adulthood (Araki et al., 2007; Sillivan and Konradi, 2011), and the D1 receptor subtype is expressed at higher levels than the D2 receptor subtype in both regions (Boyson et al., 1986; Neisewander et al., 1991; Couppis et al., 2008).”
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- cites Neisewander et al., 1991
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Fiber density increases over time in the deep layers of cortex with some fibers innervating more superficial layers in discrete cortical regions as the more superficial cortical layers develop.
“Fiber density increases over time in the deep layers of cortex with some fibers innervating more superficial layers in discrete cortical regions as the more superficial cortical layers develop (Kalsbeek et al., 1988).”
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- Premisenone given
At birth, DAergic fibers are concentrated in the developing layer VI of frontal cortex.
“At birth, DAergic fibers are concentrated in the developing layer VI of frontal cortex.”
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D1 receptor pruning is specifically associated with maturation of the excitation-inhibition balance in frontal cortex during adolescence.
“For example, D1 receptor pruning is specifically associated with maturation of the excitation-inhibition balance in frontal cortex during adolescence (Andersen et al., 2000).”
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- Interpretationreasoning
The presence of DAergic projections to the developing cortex and striatum, as well as DA receptors on precursor cells, places DA in an ideal position to modulate neuronal development, including cell proliferation, migration, and differentiation.
“The presence of DAergic projections to the developing cortex and striatum, as well as DA receptors on precursor cells, places DA in an ideal position to modulate neuronal development, including cell proliferation, migration, and differentiation all of which can lead to altered connectivity and dysfunctional synapses.”
Quote in the paperSubstantial claim - Interpretationreasoning
The evolution of the cortical DAergic system in primates suggests a more substantial role for DAergic innervation in development in more evolved species.
“This evolution of the cortical DAergic system in primates suggests a more substantial role for DAergic innervation in development in more evolved species.”
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Studies of imbalanced mesolimbic and mesocortical DAergic signaling support a potential therapeutic role for DA in reward and cognitive dysfunction in neuropsychiatric disease.
“Studies of imbalanced mesolimbic and mesocortical DAergic signaling support a potential therapeutic role for DA in reward and cognitive dysfunction in neuropsychiatric disease (Murphy et al., 1996; Volkow et al., 1998; Goldman-Rakic et al., 2004).”
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These populations send projections directly or indirectly through the globus pallidus to the substantia nigra pars reticulata and endopeduncular nucleus to make up the direct (D1) and indirect (D2) pathways to modulate movement and goal-oriented behavior.
“These populations send projections directly to or indirectly through the globus pallidus (external globus pallidus in primates) to the substantia nigra pars reticulata and endopeduncular nucleus (internal globus pallidus in primates) to make up the direct (D1 receptor expressing neurons) and indirect (D2 receptor expressing neurons) pathways to modulate movement and goal-oriented behavior (Missale”
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These DAergic afferents synapse on two distinct populations of GABAergic projection neurons, which express either D1 or D2 receptors.
“These DAergic afferents synapse on two distinct populations of GABAergic projection neurons, which express either D1 or D2 receptors (demonstrated in Figure 1D; Shuen et al., 2008; Santana et al., 2009; Ade et al., 2011).”
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In the nucleus accumbens, patterns of D1 and D2 receptor expression are similar to the dorsal striatum.
“In the nucleus accumbens, patterns of D1 and D2 receptor expression are similar to the dorsal striatum (demonstrated in Figure 1D).”
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Cortical output neurons to the nucleus accumbens express higher levels of D1 receptors during adolescence in rodent models.
“Moreover, cortical output neurons to the nucleus accumbens, a subcortical reward area, express higher levels of D1 receptors during adolescence in rodent models.”
Quote in the paperSubstantial claim - Premisecitation
Genetic and pharmacologic models of disrupted DA signaling display changes in cortical and striatal circuitry.
“In fact, genetic and pharmacologic models of disrupted DA signaling display changes in cortical and striatal circuitry (Stanwood et al., 2001b, 2005; Song et al., 2002; Kellendonk et al., 2006; McCarthy et al., 2007; Zhang et al., 2010).”
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- Interpretationreasoning
Inappropriate alterations in D1 receptor signaling during adolescent cortical maturation could play a significant role in the development of neuropsychiatric diseases.
“Thus, inappropriate alterations in D1 receptor signaling during adolescent cortical maturation could play a significant role in the development of neuropsychiatric diseases.”
Quote in the paperSubstantial claim - Interpretationreasoning
The prolonged development of the DA system allows for vulnerability into adolescence.
“This work demonstrates how the prolonged development of the DA system allows for vulnerability into adolescence.”
Quote in the paperSubstantial claim - Premisecitation
Increased D1 receptor expression in cortical output neurons to nucleus accumbens correlates with increased sensitivity to cocaine conditioned place preference.
“This correlates with increased sensitivity to cocaine conditioned place preference.”
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Raf-1, a component of the MAPK pathway that promotes mitosis, is downregulated by D1-like receptor activation.
“In addition, Raf-1, a component of the mitogen-activated protein kinase (MAPK) pathway that promotes mitosis, is downregulated by D1-like receptor activation (Denhardt, 1999; Zhang et al., 2005).”
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The two main cell types in the frontal cortex, glutamatergic pyramidal projection neurons and GABAergic interneurons, are derived from two separate progenitor pools in the developing rodent forebrain.
“The two main cell types in the frontal cortex, glutamatergic pyramidal projection neurons and GABAergic interneurons, are derived from two separate progenitor pools in the developing rodent forebrain.”
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GABAergic interneurons generated in the basal forebrain in the medial and caudal ganglionic eminences migrate tangentially to the cortex.
“Concurrently, GABAergic interneurons generated in the basal forebrain in the medial and caudal ganglionic eminences migrate tangentially to the cortex (de Carlos et al., 1996; Wonders and Anderson, 2006).”
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- Interpretationcitation
Dysregulation of either tangentially or radially migrating interneuron population would contribute to neuropsychiatric disease.
“However, this tangentially migrating population of interneurons is still a substantial portion of interneurons produced, and dysregulation of either population would contribute to neuropsychiatric disease (Hansen et al., 2013; Ma et al., 2013).”
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- Interpretationcitation
The earliest observed developmental effects of altered DA signaling are changes in neuroprogenitor proliferation.
“The earliest observed developmental effects of altered DA signaling are changes in neuroprogenitor proliferation.”
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Decreased BrdU incorporation is indicative of less neuronal progenitors undergoing division.
“Decreased BrdU incorporation is indicative of less neuronal progenitors undergoing division.”
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Selective D1-like receptor agonists can decrease incorporation of BrdU in the developing medial frontal cortex and lateral ganglionic eminence.
“Selective D1-like receptor agonists can decrease incorporation of the cell cycle marker bromodeoxyuridine (BrdU) in the developing medial frontal cortex and lateral ganglionic eminence, a basal forebrain progenitor pool that is the source for most striatal neurons (illustrated in Figure 1A).”
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The number of GABAergic interneurons increases through mammalian brain evolution beyond what the ganglionic eminences can provide.
“The number of GABAergic interneurons increases through mammalian brain evolution beyond what the ganglionic eminences can provide.”
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Anomalies in brain connectivity have been linked to several neuropsychiatric diseases, including intellectual disability and schizophrenia.
“Not surprisingly, anomalies in brain connectivity have been linked to several neuropsychiatric diseases, including intellectual disability and schizophrenia (Kaufmann and Moser, 2000; Black et al., 2004).”
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D1-like receptor stimulation alters cortical axon growth patterns by decreasing expression of the netrin-1 receptor.
“With regards to axonal effects, evidence suggests that D1-like receptor stimulation also alters cortical axon growth patterns by decreasing expression of the netrin-1 receptor (Sillivan, 2011).”
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D1-like receptor agonists significantly reduce neurite outgrowth in frontal cortical neuronal cultures.
“Several groups demonstrated that D1-like receptor agonists significantly reduce neurite outgrowth in frontal cortical neuronal cultures (Reinoso et al., 1996; Song et al., 2002; Li et al., 2013), which is depicted in Figure 1B.”
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D2-like receptor activation in primary cortical cultures leads to an increase in neurite outgrowth.
“In contrast to the growth-suppressing effects of D1-like receptor stimulation, D2-like receptor activation in primary cortical cultures leads to an increase in neurite outgrowth (illustrated in Figure 1B; Todd, 1992; Reinoso et al., 1996).”
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Altering DA receptor signaling with prenatal cocaine or receptor-specific agonists/antagonists disrupts tangential migration.
“The Bhide lab has demonstrated that altering DA receptor signaling with prenatal cocaine or receptor-specific agonists/antagonists disrupts tangential migration (illustrated in Figure 1A).”
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Overexpression of the D1 receptor by in vitro electroporation increases the effect of D1-like receptor agonists on promoting tangential migration.
“Overexpression of the D1 receptor by in vitro electroporation increases the effect of D1-like receptor agonists on promoting tangential migration (Crandall et al., 2007).”
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Increased MAP2 phosphorylation is commonly associated with decreased neurite outgrowth.
“Increased MAP2 phosphorylation is commonly associated with decreased neurite outgrowth (Sanchez et al., 2000).”
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- Interpretationreasoning
DA receptor activation modulates dendritic structure, creating subtle but significant changes in brain architecture that may increase vulnerability to neurological and/or neuropsychiatric disease.
“In fact, DA receptor activation modulates dendritic structure, creating subtle but significant changes in brain architecture that may increase vulnerability to neurological and/or neuropsychiatric disease.”
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The DA receptor-expressing population is only approximately 10-15% of neurons in the frontal cortex.
“Yet, the DA receptor-expressing population is only approximately 10–15% of neurons in the frontal cortex (Santana et al., 2009).”
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- Interpretationnone given
Activation of DA receptors influences axonal and dendritic growth in a subtype-specific manner.
“In this regard, activation of DA receptors influences axonal and dendritic growth in a subtype-specific manner.”
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Decreased neurite outgrowth is associated with destabilization of dendritic microtubule associated protein (MAP2) by increased phosphorylation.
“Song et al. (2002) further observed that decreased neurite outgrowth is associated with destabilization of dendritic microtubule associated protein (MAP2) by increased phosphorylation.”
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- Interpretationcitation
DA plays a role in spinogenesis.
“Importantly, DA plays a role in spinogenesis.”
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D2-like receptor activation shows no effect on striatal neurite outgrowth.
“However, D2-like receptor activation shows no effect on striatal neurite outgrowth (also demonstrated in Figure 1B; Schmidt et al., 1996).”
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Adolescents exposed prenatally to cocaine display changes in cortical thickness.
“In human studies, adolescents exposed prenatally to cocaine display changes in cortical thickness (Roussotte et al., 2012; Liu et al., 2013).”
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Mice overexpressing D2 receptors in the striatum have decreased complexity and length of striatal dendritic arbors.
“Finally, the Kellendonk lab has shown that mice overexpressing D2 receptors in the striatum have decreased complexity and length of striatal dendritic arbors (Cazorla et al., 2012).”
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Functional hyperdopaminergia, which occurs in DAT knockout mice, leads to a loss of proximal dendritic spines in striatal projection neurons.
“For example, a functional hyperdopaminergia, which occurs in DA transporter (DAT) knockout mice, leads to a loss of proximal dendritic spines in striatal projection neurons (Berlanga et al., 2011).”
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MAP2 labeling of D1 receptor knockout mice and diolistic labeling of rabbits prenatally exposed to cocaine show abnormal apical dendrites of cortical pyramidal cells with decreased bundling and increased tortuous patterning.
“MAP2 labeling of D1 receptor knockout mice and diolistic labeling of rabbits prenatally exposed to cocaine show abnormal apical dendrites of cortical pyramidal cells with decreased bundling and increased tortuous patterning (Jones et al., 2000; Stanwood et al., 2001a, 2005), which supports the increased basal neurite outgrowth observed in vitro.”
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Primate and rodent models of DA depletion show decreases in striatal dendritic spines.
“Primate and rodent models of DA depletion also show decreases in striatal dendritic spines (Ingham et al., 1989; Neely et al., 2007; Villalba et al., 2009).”
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D1-like receptor stimulation increases neurite outgrowth in the striatum in vitro.
“Hence, D1-like receptor stimulation increases neurite outgrowth in the striatum in vitro.”
Quote in the paperSubstantial claim - Premisecitation
This increased neurite outgrowth is associated with an increased number of growth cones and arborization.
“This increased neurite outgrowth is associated with an increased number of growth cones and arborization (Schmidt et al., 1998).”
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Alterations in spine density likely originating during development are found in many neuropsychiatric diseases, such as autism and schizophrenia.
“Additionally, alterations in spine density likely originating during development are found in many neuropsychiatric diseases, such as autism and schizophrenia (Kaufmann and Moser, 2000; Garey, 2010; Penzes et al., 2011; Glausier and Lewis, 2013; Seshadri et al., 2013).”
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Silver impregnation of cortical neurons from D1 receptor overexpressing mice show decreased apical dendrite length compared to wild type littermates.
“Conversely, silver impregnation of cortical neurons from D1 receptor overexpressing mice show decreased apical dendrite length compared to wild type littermates, which further supports a role for D1 receptor signaling to promote dendritic growth (Song et al., 2002).”
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Cortical pyramidal neurons of D1 and D2 receptor knockout mice exhibit decreased dendritic spine density.
“Cortical pyramidal neurons of D1 and D2 receptor knockout mice exhibit decreased dendritic spine density (Wang et al., 2009), and moderate D1-like and D2-like receptor activation both have been shown to increase spine density and spinophillin expression in the striatum in vitro (Fasano et al., 2013).”
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- Interpretationreasoning
A delicate balance of DA signaling is required for formation/stabilization of dendritic spines.
“Thus, a delicate balance of DA signaling is required for formation/stabilization of dendritic spines.”
Quote in the paperSubstantial claim - Premisecitation
Haloperidol, a D2-like receptor antagonist, decreases hippocampal synaptic density in vitro.
“Furthermore, haloperidol, a D2-like receptor antagonist, decreases hippocampal synaptic density in vitro (Critchlow et al., 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Critchlow et al., 2006
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- Premisecitation
Spine loss in cortical pyramidal neurons resulting from DA depletion can be ameliorated by spinogenesis-promoting antipsychotics like clozapine.
“Interestingly, the spine loss in cortical pyramidal neurons resulting from DA depletion can be ameliorated by spinogenesis-promoting antipsychotics like clozapine, providing further support for spine dysfunction in the pathology of neuropsychiatric disease (Critchlow et al., 2006; Wang and Deutch, 2008).”
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- cites Wang and Deutch, 2008
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- Premisecitation
Post mortem cortex of schizophrenic patients shows decreased dendritic spines and synaptic labeling.
“This is supported by observations of decreased dendritic spines and synaptic labeling in post mortem cortex of schizophrenic patients (Glantz and Lewis, 1997, 2000; Honer et al., 1999).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Glantz and Lewis, 1997, 2000
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- cites Honer et al., 1999
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- Interpretationcitation
Spine dysfunction is involved in the pathology of neuropsychiatric disease.
“Interestingly, the spine loss in cortical pyramidal neurons resulting from DA depletion can be ameliorated by spinogenesis-promoting antipsychotics like clozapine, providing further support for spine dysfunction in the pathology of neuropsychiatric disease (Critchlow et al., 2006; Wang and Deutch, 2008).”
Quote in the paperSubstantial claim - Premisecitation
During adolescence D2 receptor activation decreases striatal dendritic spines.
“In fact, during adolescence D2 receptor activation decreases striatal dendritic spines (Jia et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jia et al., 2013
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- Premisecitation
DA lesion studies in adult animals support a continued role for DA in maintenance of corticostriatal synapses in the striatum.
“DA lesion studies in adult animals support a continued role for DA in the maintenance of corticostriatal synapses in the striatum (for a comprehensive review of DA-regulated morphological and electrophysiological changes, please see Arbuthnott et al., 2000 and Surmeier et al., 2011).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Arbuthnott et al., 2000
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- cites Surmeier et al., 2011
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Moderate D1-like and D2-like receptor activation both increase spine density and spinophillin expression in the striatum in vitro.
“Cortical pyramidal neurons of D1 and D2 receptor knockout mice exhibit decreased dendritic spine density (Wang et al., 2009), and moderate D1-like and D2-like receptor activation both have been shown to increase spine density and spinophillin expression in the striatum in vitro (Fasano et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fasano et al., 2013
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- Interpretationcitation
Inappropriate dendritic arborization, spinogenesis, and synaptic connections lead to inappropriate connectivity and altered excitation-inhibition balance.
“Inappropriate dendritic arborization, spinogenesis, and synaptic connections lead to inappropriate connectivity and altered excitation-inhibition balance (McGlashan and Hoffman, 2000; Spronsen and Hoogenraad, 2010; Duman and Aghajanian, 2012).”
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- cites Spronsen and Hoogenraad, 2010
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- cites Duman and Aghajanian, 2012
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- Interpretationreasoning
Schizophrenia and other neurodevelopmental disorders are at least in part diseases of altered synaptic connectivity.
“Schizophrenia and other neurodevelopmental disorders are at least in part, diseases of altered synaptic connectivity.”
Quote in the paperSubstantial claim - Premisecitation
DAT polymorphisms are linked to both ADHD and bipolar disorder.
“and DAT polymorphisms linked to both ADHD and bipolar disorder (Sharp et al., 2009).”
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- Premisecitation
Polymorphisms in the gene encoding Akt are associated with both bipolar disorder and schizophrenia.
“Additionally, polymorphisms in the gene encoding the downstream signaling protein Akt are associated with both bipolar disorder and schizophrenia (Thiselton et al., 2008; Karege et al., 2012).”
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- cites Karege et al., 2012
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Emerging data implicates D1-like receptors as a target for negative symptoms in schizophrenia.
“While D2 receptor antagonism may be useful in controlling many of the positive symptoms in schizophrenia, emerging data implicates D1-like receptors as a target for negative symptoms in schizophrenia (Goldman-Rakic et al., 2004; Arnsten, 2013).”
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- cites Arnsten, 2013
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Both D1-like receptor agonists and PKA activators increase cortical MAP2 phosphorylation, decreasing MAP2 stabilization of the dendritic cytoskeleton and thus decreasing neurite outgrowth.
“Both D1-like receptor agonists and PKA activators increase cortical MAP2 phosphorylation, decreasing the ability of MAP2 to stabilize the dendritic cytoskeleton and thus decreasing neurite outgrowth (Song et al., 2002).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Song et al., 2002
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- Premisecitation
Polymorphisms in DRD3 and DRD4 are associated with autism severity.
“Others have found polymorphisms in DRD3 and DRD4 associated with autism severity (de Krom et al., 2009; Gadow et al., 2010; Staal et al., 2012)”
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- cites Gadow et al., 2010
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- cites Staal et al., 2012
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- Interpretationreasoning
Taken together, these findings emphasize that disrupted DAergic homeostasis may be a central mechanism in the risk of developing a neuropsychiatric disorder.
“While the effect sizes in these studies are not large, and the link to DA is sometimes indirect, taken together these findings emphasize that disrupted DAergic homeostasis may be a central mechanism in the risk of developing a neuropsychiatric disorder.”
Quote in the paperSubstantial claim - Premisecitation
Dephosphorylation of AKT increases activity of GSK3, a target of lithium and many antipsychotic drugs.
“The resulting dephosphorylation of AKT increases activity of GSK3, a target of lithium and many antipsychotic drugs (Beaulieu et al., 2004; Li et al., 2007; Lovestone et al., 2007).”
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- cites Li et al., 2007
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- cites Lovestone et al., 2007
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Increased neurite outgrowth in striatal cultures is at least partially dependent on D1 receptor-mediated neurotrophin TrkB receptor activation.
“Additionally, the Chao lab has demonstrated that increased neurite outgrowth in striatal cultures is at least partially dependent on D1 receptor-mediated neurotrophin TrkB receptor activation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Iwakura et al., 2008
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- Interpretationreasoning
DA does not provide a singular role in these developmental processes.
“DA thus does not provide a singular role in these developmental processes, and future studies will need to address additional neuromodulators in combinatorial patterns.”
Quote in the paperSubstantial claim - Premisecitation
Association studies implicate the A1 allele of the Taq1 polymorphism of DRD2 in the development of Tourette's syndrome, ADHD, autism, PTSD, and alcoholism.
“Association studies implicate the A1 allele of the Taq1 polymorphism of DRD2 in the development of Tourette’s syndrome, ADHD, autism, PTSD, and alcoholism (Comings et al., 1991).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Comings et al., 1991
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- Interpretationreasoning
Given profound differences between how neurites of cortical and striatal neurons respond to DA receptor agonists, intracellular signals are likely regulated in cell-specific ways.
“Given the profound differences between how neurites of cortical and striatal neurons respond to DA receptor agonists, it is likely that intracellular signals are regulated in cell-specific ways.”
Quote in the paperSubstantial claim - Premisecitation
Hypomethylation of the COMT gene, which increases the enzyme that breaks down DA, has been associated with schizophrenia and bipolar disorder.
“Hypomethylation of the COMT gene, which leads to an increase in the enzyme that breaks down DA, has been associated with schizophrenia and bipolar disorder (Abdolmaleky et al., 2006; Nohesara et al., 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Abdolmaleky et al., 2006
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- cites Nohesara et al., 2011
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- Interpretationreasoning
There is strong evidence that DA plays a critical role in the generation of typical brain structure and function.
“There is strong evidence that DA plays a critical role in the generation of typical brain structure and function.”
Quote in the paperSubstantial claim - Interpretationreasoning
Altered DA signaling can affect the proliferation, migration, and differentiation of specific subpopulations of neurons, and thus impact frontal cortex and striatal neurocircuitry.
“Altered DA signaling can affect the proliferation, migration, and differentiation of specific subpopulations of neurons, and thus impact frontal cortex and striatal neurocircuitry.”
Quote in the paperSubstantial claim - Premisecitation
DA-related genes DRD1, DRD2, and PPP1R1B are associated with the severity of autism in families with males only affected.
“The Holden lab has found DA-related genes (DRD1, DRD2, and PPP1R1B) associated with the severity of autism in families with males only affected (Hettinger et al., 2008, 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hettinger et al., 2008, 2012
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- Interpretationnone given
D1 and D2 receptor subtypes often have opposing effects on developmental processes.
“D1 and D2 receptor subtypes often have opposing effects on these developmental processes, and the underlying mechanism for this dichotomy as well as the signaling pathways that mediate these subtype-specific effects remain mostly unknown.”
Quote in the paperSubstantial claim - Premisecitation
Patients with 22q11 deletion syndrome, which disrupts DA-related genes including COMT, have an increased risk for neuropsychiatric disorders including schizophrenia-like psychosis, autism, and anxiety disorders.
“Patients with 22q11 deletion syndrome, which disrupts DA-related genes (e.g., catechol-O-methyltransferase, COMT) among others have an increased risk for neuropsychiatric disorders, including schizophrenia-like psychosis, autism, and anxiety disorders (Karam et al., 2010; Jonas et al., 2013).”
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- cites Jonas et al., 2013
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- Premisecitation
DA-rich areas, such as the prefrontal cortex and striatum, are clearly dysfunctional in neuropsychiatric disorders like schizophrenia, substance use disorders, and ADHD.
“DA-rich areas, such as the prefrontal cortex and striatum, are clearly dysfunctional in neuropsychiatric disorders like schizophrenia, substance use disorders, and ADHD (Arnsten, 2006, 2011; Leppanen, 2006; Andersen and Teicher, 2009; Arnsten et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Arnsten, 2006, 2011
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- cites Leppanen, 2006
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- cites Andersen and Teicher, 2009
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- Premisecitation
D1 receptors interact with NMDA receptors, adenosine receptors, and neurotrophin TrkB receptors, among others.
“For example, D1 receptors interact with NMDA receptors (Lee et al., 2002; Nai et al., 2010), adenosine receptors (Fuxe et al., 2007; Shen et al., 2013), and neurotrophin TrkB receptors (Iwakura et al., 2008), among others.”
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- cites Nai et al., 2010
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- cites Fuxe et al., 2007
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- Premisecitation
Early interventions have the most positive impacts in neurodevelopmental disorders and learning disabilities.
“Importantly, early interventions have the most positive impacts in neurodevelopmental disorders and learning disabilities (Bradshaw et al., 2012)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bradshaw et al., 2012
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- Premisecitation
Developmental alterations in dendritic growth and/or GABAergic interneuron migration likely contribute to the development of pathology in these disorders.
“Developmental alterations in dendritic growth and/or GABAergic interneuron migration likely contribute to the development of pathology in these disorders (Beasley and Reynolds, 1997; Kaufmann and Moser, 2000; Black et al., 2004; Curley et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Beasley and Reynolds, 1997
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- cites Kaufmann and Moser, 2000
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- Classified as probably not a substantial claim. 15
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PremisecitationRepeated exposure to methylphenidate during the juvenile period reduces cocaine reward in adulthood, whereas adult methylphenidate exposure does not confer this protection.
“For example, a landmark study by Andersen et al. (2002) showed that repeated exposure to methylphenidate (Ritalin) during the juvenile period reduces cocaine reward in adulthood, whereas adult methylphenidate exposure does not confer this protection.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Andersen et al. (2002)
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PremisecitationThe frontal/prefrontal cortex and striatum receive prominent dopamine innervations and express dopamine receptors.
“These brain regions receive prominent dopamine (DA) innervations and express DA receptors (Bjorklund and Dunnett, 2007; Tritsch and Sabatini, 2012; Roeper, 2013).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Bjorklund and Dunnett, 2007
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- cites Tritsch and Sabatini, 2012
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- cites Roeper, 2013
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PremisecitationA decrease in DAergic axons in deep layers of medial prefrontal cortex and decreased D1 receptor binding occurs in schizophrenic patients.
“A decrease in DAergic axons in deep layers of medial prefrontal cortex and decreased D1 receptor binding occurs in schizophrenic patients (Okubo et al., 1997; Akil et al., 1999).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Okubo et al., 1997
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- cites Akil et al., 1999
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PremisecitationSuch disruption can lead to long-lasting, even permanent, effects and contribute to brain disorders later in life.
“In turn, this can lead to long-lasting, even permanent, effects and contribute to brain disorders later in life (Finlay, 2001; Lewis and Levitt, 2002; Frederick and Stanwood, 2009; Thompson et al., 2009; Rapoport et al., 2012; Ben-Ari, 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Finlay, 2001
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- cites Lewis and Levitt, 2002
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Premisenone givenDA innervation and receptor expression are present early in development, mature during adolescence, and form stable patterns in young adulthood.
“DA innervation and receptor expression are present early in development, mature during adolescence, and form stable patterns in young adulthood.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationD3 and D5 receptor mRNA is first found in the striatum at E12 and frontal cortex by E15.
“For example, D3 and D5 receptor mRNA is first found in the striatum at E12 and frontal cortex by E15 (Araki et al., 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Araki et al., 2007
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PremisecitationD3, D4, and D5 receptors are consistently expressed at lower levels but are present even during prenatal development.
“D3, D4, and D5 receptors are consistently expressed at lower levels but still are present even during prenatal development.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationD4 receptor mRNA decreases after birth with a more significant drop in expression in the frontal cortex.
“D4 receptor mRNA decreases after birth with a more significant drop in expression seen in the frontal cortex (Nair and Mishra, 1995).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nair and Mishra, 1995
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PremisecitationDopaminergic development continues postnatally and impacts forebrain synaptogenesis and connectivity.
“Dopaminergic development continues postnatally and impacts forebrain synaptogenesis and connectivity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenStudies in other species suggest that these sequences of events are very well conserved evolutionarily, although the exact timings differ based on gestation length.
“Studies in other species suggest that these sequences of events are very well conserved evolutionarily, although the exact timings are of course quite different based on gestation length (see below).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationD4 receptor mRNA is present in the striatum at E12 and frontal cortex by E15, and has its highest expression during embryonic development.
“However, D4 receptor mRNA, which is also present in the striatum at E12 and frontal cortex by E15, has its highest expression during embryonic development (Araki et al., 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Araki et al., 2007
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Premisenone givenThe rat developing cortex receives DAergic fibers that pass through the striatum, with innervation occurring in a lateral (E16) to medial fashion (E19).
“The rat developing cortex receives DAergic fibers that pass through the striatum, with innervation occurring in a lateral (E16) to medial fashion (E19).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationHuman DAergic innervation occurs early in development and is strongly established by mid-gestation.
“Human DAergic innervation occurs early in development and is strongly established by mid-gestation (Olson et al., 1973; Verney et al., 1991, 1993; Zecevic and Verney, 1995).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Olson et al., 1973
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- cites Verney et al., 1991
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- cites Zecevic and Verney, 1995
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InterpretationreasoningDA can influence multiple aspects of human behavior both directly through striatal projections and indirectly through alterations in reward and cognition.
“Thus, DA can influence multiple aspects of human behavior both directly through striatal projections and indirectly through alterations in reward and cognition (for description of the trajectories of growing DA axons and signals contributing to topography, see Prestoz et al., 2012).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenThe ventral tegmental area gives rise to two additional DAergic pathways: mesolimbic and mesocortical.
“The ventral tegmental area (VTA), another mesencephalic nucleus, gives rise to two additional DAergic pathways. Projections from the VTA to limbic areas, such as the nucleus accumbens, and to the frontal cortex form the mesolimbic and mesocortical pathways (shown in Figure 2), respectively.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAberrant reward processing drives substance abuse disorders, and cognitive dysfunction exists as an often overlooked but devastating feature of many neuropsychiatric disorders.
“Aberrant reward processing drives substance abuse disorders, and cognitive dysfunction exists as an often overlooked but devastating feature of many neuropsychiatric disorders (Carter et al., 1998; Bosboom et al., 2004; Medalia and Lim, 2004).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Carter et al., 1998
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- cites Bosboom et al., 2004
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- cites Medalia and Lim, 2004
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PremisecitationThe shell of the nucleus accumbens expresses high levels of D3 receptors.
“In addition, the shell of the nucleus accumbens expresses high levels of D3 receptors (Le Moine and Bloch, 1995).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Le Moine and Bloch, 1995
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Interpretationnone givenThe increased influence of DA in the human brain is exemplified by the increase in neuropsychiatric disease onset during adolescence, the time period when the DA system matures.
“The increased influence of DA in the human brain is exemplified by the increase in neuropsychiatric disease onset during adolescence, the time period when the DA system matures.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationEnvironmental, social, and inflammatory challenges during sensitive periods of forebrain development produce neuro(mal)adaptions in these regions and phenocopy some aspects of brain disorders.
“Environmental, social, and inflammatory challenges during sensitive periods of forebrain development also produce neuro(mal)adaptions in these regions and phenocopy some aspects of brain disorders (Di Forti et al., 2007; Kern et al., 2010; Han et al., 2012; Selemon and Friedman, 2013).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Di Forti et al., 2007
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- cites Kern et al., 2010
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- cites Han et al., 2012
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Premisenone givenDA receptor expression is lower in the frontal cortex and found in several types of neurons.
“DA receptor expression is lower in the frontal cortex and found in several types of neurons.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenThe striatum receives DAergic innervation from the substantia nigra pars compacta (nigrostriatal pathway).
“The striatum receives DAergic innervation from the substantia nigra pars compacta, which is known as the nigrostriatal pathway (shown in Figure 2).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe density of DAergic fibers to the prefrontal cortex in non-human primates increases during preadolescence, peaks during adolescence, and then declines.
“The density of DAergic fibers to the prefrontal cortex in non-human primates increases during preadolescence, peaks during adolescence, and then declines (Rosenberg and Lewis, 1995).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rosenberg and Lewis, 1995
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PremisereasoningDA is one of the earliest neurotransmitters expressed in the developing brain and plays a significant role in the development of neuronal cytoarchitecture.
“DA is one of the earliest neurotransmitters expressed in the developing brain and plays a significant role in the development of neuronal cytoarchitecture.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationD4 and D5 receptors are expressed at low levels in frontal cortex.
“D4 and D5 receptors are expressed at low levels in frontal cortex (Beaulieu and Gainetdinov, 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Beaulieu and Gainetdinov, 2011
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PremisecitationMicroinjections of D1-like receptor agonist in the prefrontal cortex enhance cocaine conditioned place preference, while D1-like receptor antagonist blunts it.
“Brenhouse et al. (2008) found this increased preference to be enhanced with microinjections of D1-like receptor agonist in the prefrontal cortex but blunted with D1-like receptor antagonist, demonstrating the importance of D1 receptor signaling in heightened adolescent sensitivity to cocaine preference.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Brenhouse et al. (2008)
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PremisecitationMonkeys and humans have more widespread cortical DA input than rodents and significantly denser DAergic innervation in motor, premotor, and supplementary motor association cortices.
“In regards to DA, monkeys and humans have more widespread cortical DA input than rodents and significantly denser DAergic innervation in motor, premotor, and supplementary motor association cortices (Berger et al., 1988, 1991; Gaspar et al., 1989; Meador-Woodruff et al., 1996).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Berger et al., 1988
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- cites Gaspar et al., 1989
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- cites Meador-Woodruff et al., 1996
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PremisecitationIn the frontal cortex, D1 receptors appear to be the most prominent DA receptor, and both D1 and D2 receptors are found in deep layer V/VI glutamatergic projection neurons and parvalbumin-containing GABAergic interneurons.
“In the frontal cortex, D1 receptors appear to be the most prominent DA receptor, and both D1 and D2 receptors are found in deep layer V/VI glutamatergic projection neurons and parvalbumin-containing GABAergic interneurons (Le Moine and Gaspar, 1998; Muly et al., 1998).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Le Moine and Gaspar, 1998
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- cites Muly et al., 1998
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Premisenone givenThe mesolimbic pathway is mainly associated with reward, while the mesocortical pathway is associated with cognitive function.
“The mesolimbic pathway is mainly associated with reward, while the mesocortical pathway is associated with cognitive function.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBoth acute and chronic DA depletion decreases subependymal neuronal proliferation.
“And although it is beyond the scope of our current review, it is also worth noting that both acute and chronic DA depletion decreases subependymal neuronal proliferation (Lewis et al., 1977; Patel et al., 1977), and DA receptors, especially D3 receptors, can guide adult neurogenesis as well (Kim et al., 2010; Egeland et al., 2012; Lao et al., 2013).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Lewis et al., 1977
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- cites Patel et al., 1977
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PremisecitationModels of prenatal infection, stress, and exposure to drugs of abuse show long-lasting changes in DA receptor expression and function and have been associated with increased risk for psychiatric disorders.
“For example, models of prenatal infection, stress, and exposure to drugs of abuse show long-lasting changes in DA receptor expression and function and have been associated with increased risk for psychiatric disorders (Alonso et al., 1994; Stanwood et al., 2001b; Berger et al., 2002; Zuckerman et al., 2003; Andersen and Teicher, 2009; Bhide, 2009; Brown et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Alonso et al., 1994
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- cites Stanwood et al., 2001b
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- cites Berger et al., 2002
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PremisecitationD1-like receptor activation promotes downregulation of cyclin D and upregulation of the cyclin dependent kinase inhibitor p27Kip1.
“Indeed, D1-like receptor activation promotes downregulation of cyclin D and upregulation of the cyclin dependent kinase inhibitor p27Kip1 (Zhang et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang et al., 2005
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Premisenone givenPyramidal neurons are produced locally in the neuroepithelium of the developing cortex and migrate radially to the appropriate cortical layer.
“Pyramidal neurons are produced locally in the neuroepithelium of the developing cortex and migrate radially to the appropriate cortical layer.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S1 (asserted).
InterpretationreasoningDAergic modulation of developmental processes produces long-lasting alterations that contribute to cortical and striatal dysfunction in neuropsychiatric disorders.
“Taken together, these data have led our group and others to hypothesize that DAergic modulation of developmental processes produces long lasting alterations that contribute to cortical and striatal dysfunction in neuropsychiatric disorders.”
Quote in the paperNot a substantial claim- Rests on an assumption: Findings from rodent and in vitro models of DA signaling disruption can be extrapolated to human neuropsychiatric disorders.
- Rests on an assumption: Alterations in DA signaling during development are causally involved in neuropsychiatric disorders, rather than merely correlated.
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PremisecitationCyclin D promotes the transition from the growth phase to S-phase of the cell cycle while p27Kip1 inhibits it.
“Cyclin D promotes the transition from the growth phase to S-phase of the cell cycle while p27Kip1 inhibits it (Sheaff and Roberts, 1998).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sheaff and Roberts, 1998
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Interpretationnone givenSmall deviations in the number of cells available to release or receive important developmental signals could significantly alter developmental trajectory.
“The effects of transient differences in cell cycle proteins have yet to be understood, but small deviations in the number of cells available to release or receive important developmental signals could significantly alter developmental trajectory.”
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InterpretationcitationInappropriate excitation-inhibition balance in frontal cortex is found in several neuropsychiatric diseases, which could be partly due to a lack of adequate interneuron migration.
“As mentioned above, inappropriate excitation-inhibition balance in frontal cortex is found in several neuropsychiatric diseases (Harada et al., 2011; Cornew et al., 2012; Radhu et al., 2013), which could be partly due to a lack of adequate interneuron migration.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Harada et al., 2011
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- cites Cornew et al., 2012
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- cites Radhu et al., 2013
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PremisecitationBoth D1-like and D2-like receptors contribute to neurogenesis but with opposite effects; blockade of D1-like receptors and activation of D2-like receptors increase the number of neuronal progenitors undergoing cell division.
“Both D1-like and D2-like receptors contribute to neurogenesis but with opposite effects; blockade of D1-like receptors and activation of D2-like receptors increase the number of neuronal progenitors undergoing cell division (Ohtani et al., 2003; Popolo et al., 2004).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Ohtani et al., 2003
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- cites Popolo et al., 2004
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PremisecitationIn primates, GABAergic interneurons are also produced in the dorsal forebrain and migrate radially through cortex.
“Therefore, in primates, GABAergic interneurons are also produced in the dorsal forebrain and migrate radially through cortex (Letinic et al., 2002; Petanjek et al., 2009).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Letinic et al., 2002
Not checked in the free run.
- cites Petanjek et al., 2009
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDA receptors, especially D3 receptors, can guide adult neurogenesis.
“And although it is beyond the scope of our current review, it is also worth noting that both acute and chronic DA depletion decreases subependymal neuronal proliferation (Lewis et al., 1977; Patel et al., 1977), and DA receptors, especially D3 receptors, can guide adult neurogenesis as well (Kim et al., 2010; Egeland et al., 2012; Lao et al., 2013).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Kim et al., 2010
Not checked in the free run.
- cites Egeland et al., 2012
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- cites Lao et al., 2013
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May combine two claims.
PremisecitationAdministration of the DA precursor L-DOPA during early gestation decreases cell proliferation, suggesting that D1 receptor mediated effects may dominate in vivo.
“Administration of the DA precursor L-DOPA during early gestation decreases cell proliferation (McCarthy et al., 2007), suggesting that D1 receptor mediated effects may dominate in vivo.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites McCarthy et al., 2007
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThis subtype-specific redistribution of cytoskeletal elements needed for cell motility leads to opposite effects on neuronal migration.
“Crandall et al. (2007) suggest that this subtype-specific redistribution of cytoskeletal elements needed for cell motility leads to opposite effects on neuronal migration.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Crandall et al. (2007)
Not checked in the free run.
May combine two claims.
PremisecitationAn animal model of prenatal cocaine exposure produces a long-lasting uncoupling of D1 receptor signaling and concomitant increase in neurite outgrowth.
“An animal model of prenatal cocaine exposure also demonstrates the importance of cortical D1 receptor signaling to suppress neurite outgrowth. This model produces a long-lasting uncoupling of D1 receptor signaling and concomitant increase in neurite outgrowth (Jones et al., 2000; Stanwood and Levitt, 2007).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Jones et al., 2000
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- cites Stanwood and Levitt, 2007
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May combine two claims.
PremisecitationApplication of D1-like receptor agonists in mouse embryonic slice cultures promotes cortical GABAergic neuron migration whereas D2-like receptor agonism decreases migration.
“In addition, application of D1-like receptor agonists in mouse embryonic slice cultures promotes cortical GABAergic neuron migration whereas D2-like receptor agonism decreases migration (Crandall et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Crandall et al., 2007
Not checked in the free run.
May combine two claims.
PremisecitationActivation of numerous kinases causes MAP2 phosphorylation, providing an effector but not the mechanism.
“However, activation of numerous kinases causes MAP2 phosphorylation, providing an effector but not the mechanism (Sanchez et al., 2000).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sanchez et al., 2000
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Premisenone givenCytoskeletal reorganization must occur for neuronal migration.
“The basis for opposing D1 vs. D2 receptor effects is not fully understood, but cytoskeletal reorganization must occur for neuronal migration.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationDendritic and axonal growth are activity-dependent, highly dynamic processes that remain partially plastic until adulthood.
“Dendritic and axonal growth are activity-dependent, highly dynamic processes that remain partially plastic until adulthood (McAllister, 2000).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites McAllister, 2000
Not checked in the free run.
May combine two claims.
PremisecitationD1-like receptor stimulation leads to increased neurite localization of cytoskeletal elements needed for cell motility, such as cytoplasmic dynein motor protein and tubulin, whereas D2-like receptor stimulation leads to increased cell body localization of these cytoskeletal elements.
“D1-like receptor stimulation leads to increased neurite localization of cytoskeletal elements needed for cell motility, such as cytoplasmic dynein motor protein and tubulin, whereas D2-like receptor stimulation leads to increased cell body localization of these cytoskeletal elements.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPrenatal cocaine exposure decreases tangential migration of cortical GABAergic neurons, perhaps mediated by the loss of D1 receptor signaling.
“Prenatal cocaine exposure decreases tangential migration of cortical GABAergic neurons, perhaps mediated by the loss of D1 receptor signaling (Jones et al., 2000; Crandall et al., 2004; Stanwood and Levitt, 2007; McCarthy et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Jones et al., 2000
Not checked in the free run.
- cites Crandall et al., 2004
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- cites Stanwood and Levitt, 2007
Not checked in the free run.
May combine two claims.
InterpretationcitationD1-like receptor stimulation decreases neurite outgrowth and netrin-1 receptor expression whereas D2-like receptor stimulation increases neurite outgrowth in vitro.
“Thus, D1-like receptor stimulation decreases neurite outgrowth and netrin-1 receptor expression whereas D2-like receptor stimulation increases neurite outgrowth in vitro.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationApplication of D1-like receptor agonists to striatal neuronal cultures promotes neurite outgrowth, which can be blocked with D1-like receptor antagonists.
“In contrast, application of D1-like receptor agonists to striatal neuronal cultures promotes neurite outgrowth, which can be blocked with D1-like receptor antagonists and is demonstrated in Figure 1B (Schmidt et al., 1996, 1998).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Schmidt et al., 1996
Not checked in the free run.
- cites Schmidt et al., 1998
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May combine two claims.
Premisenone givenGABAergic neurons in the medial and caudal ganglionic eminences express DA receptors, and these forebrain regions receive DAergic innervation during the embryonic period when migration occurs.
“GABAergic neurons in the medial and caudal ganglionic eminences express DA receptors, and these forebrain regions receive DAergic innervation during the embryonic period when migration occurs.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSpines develop from dendritic filopodia that interact with incoming axons, but some data suggest that dendritic spines can form independent of axonal interaction.
“Spines develop from dendritic filopodia that interact with incoming axons, but some data suggest that dendritic spines can form independent of axonal interaction (Zhang and Benson, 2000; Whitford et al., 2002; Yuste and Bonhoeffer, 2004).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Zhang and Benson, 2000
Not checked in the free run.
- cites Whitford et al., 2002
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- cites Yuste and Bonhoeffer, 2004
Not checked in the free run.
May combine two claims.
PremisecitationModels of DA depletion show decreased expression of axon guidance- and cytoskeletal growth-related proteins as well as decreased length of pyramidal layer V basal dendrites in frontal cortex.
“Models of DA depletion (i.e., 6-OHDA treatment or mesencephalic lesion) show decreased expression of axon guidance- and cytoskeletal growth-related proteins as well as decreased length of pyramidal layer V basal dendrites in frontal cortex (Kalsbeek et al., 1989; Krasnova et al., 2007).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Kalsbeek et al., 1989
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- cites Krasnova et al., 2007
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May combine two claims.
PremisecitationThe DAT knockout model also shows a behavioral phenotype of hyperactivity and anxiety as well as altered mesocortical circuitry, and DA dysregulation occurs not only during development, but continues into adulthood in this model.
“This model also shows a behavioral phenotype of hyperactivity and anxiety as well as altered mesocortical circuitry (Zhang et al., 2010; Carpenter et al., 2012), and DA dysregulation occurs not only during development, but continues into adulthood in this model.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Zhang et al., 2010
Not checked in the free run.
- cites Carpenter et al., 2012
Not checked in the free run.
May combine two claims.
PremisecitationDendritic spines are critical for synaptic plasticity, allowing for compartmentalization of post-synaptic signaling and synaptic specialization.
“Dendritic spines are critical for synaptic plasticity, allowing for compartmentalization of post-synaptic signaling and synaptic specialization (Yuste and Bonhoeffer, 2001).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yuste and Bonhoeffer, 2001
Not checked in the free run.
May combine two claims.
PremisecitationDendritic spinous processes start to form at the beginning of synaptogenesis during the first postnatal week and peak in adolescence but continue to be structurally modified throughout adulthood.
“Dendritic spinous processes start to form at the beginning of synaptogenesis during the first postnatal week and peak in adolescence but continue to be structurally modified throughout adulthood (Zhang and Benson, 2000).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhang and Benson, 2000
Not checked in the free run.
May combine two claims.
PremisecitationMAPKs like ERK are activated by D1 receptor stimulation and increase CREB signaling.
“Additionally, MAPKs like extracellular signal-related kinase (ERK) are activated by D1 receptor stimulation and increase CREB signaling (Missale et al., 1998).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Missale et al., 1998
Not checked in the free run.
May combine two claims.
InterpretationreasoningSynaptogenesis can be altered by developmental events and plays an important role in neuropsychiatric disease pathology.
“Thus, synaptogenesis can be altered by any of the previously discussed developmental events and plays an important role in neuropsychiatric disease pathology.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNeonatal DA depletion decreases the number of symmetric synapses and changes the structure of asymmetric synapses.
“Neonatal DA depletion decreases the number of symmetric synapses and changes the structure of asymmetric synapses (Onténiente et al., 1980; Tennyson et al., 1982; Ingham et al., 1991, 1993).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Onténiente et al., 1980
Not checked in the free run.
- cites Tennyson et al., 1982
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- cites Ingham et al., 1991, 1993
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationD2-like receptors typically transduce signals by inhibiting adenylyl cyclase and decreasing cAMP.
“Conversely, D2-like receptors typically transduce their signals by inhibiting adenylyl cyclase and decreasing cAMP (Missale et al., 1998; Beaulieu and Gainetdinov, 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Missale et al., 1998
Not checked in the free run.
- cites Beaulieu and Gainetdinov, 2011
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationD1-like receptors transduce signals by activating adenylyl cyclase and increasing intracellular cAMP via Gαs/Gαolf coupled proteins.
“In general, D1-like receptors transduce their signals by activating adenylyl cyclase and increasing intracellular cAMP via Gαs/Gαolf coupled proteins.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Missale et al., 1998
Not checked in the free run.
- cites Beaulieu and Gainetdinov, 2011
Not checked in the free run.
May combine two claims.
PremisecitationDA receptor antagonists can decrease prefrontal synapse density whereas agonists slightly increase density.
“DA receptor antagonists can decrease prefrontal synapse density whereas agonists slightly increased density (Sugahara and Shiraishi, 1998).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sugahara and Shiraishi, 1998
Not checked in the free run.
May combine two claims.
InterpretationreasoningTaken together, studies support a crucial role for DA in formation and stabilization of synaptic connections in the striatum and frontal cortex, providing evidence for developmental disruptions of DA and other neurotransmitters in the structural pathology of neuropsychiatric disease.
“Taken together, these studies support a crucial role for DA in formation and stabilization of synaptic connections in the striatum and frontal cortex, providing further evidence for developmental disruptions of DA and other neurotransmitters in the structural pathology of neuropsychiatric disease.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationD2 receptors complex with adenosine A2A receptors and sigma-1 receptors and recruit AKT/GSK3 signaling pathways via a slower, cAMP-independent signaling mechanism.
“D2 receptors complex with adenosine A2A receptors (Canals et al., 2003) and sigma-1 receptors (Navarro et al., 2013) and recruit protein kinase B/glycogen synthase kinase 3 (AKT/GSK3) signaling pathways via a slower, cAMP-independent signaling mechanism (Beaulieu et al., 2005, 2007).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Canals et al., 2003
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- cites Navarro et al., 2013
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- cites Beaulieu et al., 2005, 2007
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May combine two claims.
Interpretationnone givenThe DA system plays a fundamental role in psychotic disorders, with D2 receptor antagonism being a major target for both typical and atypical antipsychotics.
“The DA system plays a fundamental role in psychotic disorders, with D2 receptor antagonism being a major target for both typical and atypical antipsychotics.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationKnockdown of DISC-1 in animal models causes altered DAergic maturation and behavioral changes associated with altered prefrontal cortex circuitry, suggesting a role for DA in DISC-1 associated neuropsychiatric disease.
“Interestingly, knockdown of DISC-1 in animal models causes altered DAergic maturation and behavioral changes associated with altered prefrontal cortex circuitry, suggesting a role for DA in DISC-1 associated neuropsychiatric disease (Niwa et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Niwa et al., 2010
Not checked in the free run.
May combine two claims.
InterpretationcitationTaken together, D1-like receptor-mediated changes in neurite outgrowth are PKA-dependent in both cortex and striatum with an additional neurotrophin TrkB receptor-dependent component only in the striatum.
“Thus, taken together, current evidence suggests that the D1-like receptor-mediated changes in neurite outgrowth are PKA-dependent in both cortex and striatum with an additional neurotrophin TrkB receptor-dependent component only in the striatum.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSerotonin is present before synaptogenesis and alters neurite outgrowth and axon pathfinding in vitro in a receptor-dependent manner.
“Serotonin is present before synaptogenesis (Hansson et al., 1998) and alters neurite outgrowth and axon pathfinding in vitro in a receptor-dependent manner”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Hansson et al., 1998
Not checked in the free run.
- cites Lotto et al., 1999
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- cites Persico et al., 2006
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May combine two claims.
PremisecitationNeurite outgrowth facilitation by D1-like receptor stimulation in the striatum is PKA-dependent and at least in part CREB-mediated.
“Neurite outgrowth facilitation by D1-like receptor stimulation in the striatum is also PKA-dependent and at least in part CREB-mediated (Schmidt et al., 1998).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Schmidt et al., 1998
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe increased DAergic influence in the cortex of primates and dysfunction of DA-rich cortical areas in neuropsychiatric disorders suggests an evolutionally increased role of DA, which has also resulted in an evolutionarily increased vulnerability to disease.
“The increased DAergic influence in the cortex of primates and dysfunction of DA-rich cortical areas in neuropsychiatric disorders suggests an evolutionally increased role of DA, which has also resulted in an evolutionarily increased vulnerability to disease.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Findings from rodent and in vitro models of DA signaling disruption can be extrapolated to human neuropsychiatric disorders.
“Taken together, these data have led our group and others to hypothesize that DAergic modulation of developmental processes produces long lasting alterations that contribute to cortical and striatal dysfunction in neuropsychiatric disorders.”
The paper relies on this without support.
Alterations in DA signaling during development are causally involved in neuropsychiatric disorders, rather than merely correlated.
“Thus, inappropriate alterations in D1 receptor signaling during adolescent cortical maturation could play a significant role in the development of neuropsychiatric diseases.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In many neurodevelopmental disorders (NDDs) the developing dopamine system is affected, playing a role in the diverse symptoms of these disorders.
“In many neurodevelopmental disorders (NDDs) the developing dopamine system is affected playing a role in the diverse symptoms of these disorders [179].”
From Development of prefrontal cortex (2022) · cites this paper as [179]
The Introduction and the section on genetic disruptions of dopamine signaling link dopamine-related changes to several neuropsychiatric disorders and their behavioral effects (page numbers not supplied). But the Introduction says links to specific diseases are often indirect and poorly understood, while the Conclusion says understanding of developmental dopamine disruption is still maturing. The claim presents an effect on the developing dopamine system across many disorders more definitively than the paper does. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Cortical D1 signaling is described as both promoting and suppressing dendritic growth
MinorThe paper says shorter cortical dendrites in D1-overexpressing mice support a role for D1 signaling in promoting dendritic growth. Elsewhere, it concludes that D1-like receptor stimulation decreases cortical neurite outgrowth. The reported shorter dendrites support suppression, not promotion, of growth.
“Conversely, silver impregnation of cortical neurons from D1 receptor overexpressing mice show decreased apical dendrite length compared to wild type littermates, which further supports a role for D1 receptor signaling to promote dendritic growth (Song et al., 2002).”
“Thus, D1-like receptor stimulation decreases neurite outgrowth and netrin-1 receptor expression whereas D2-like receptor stimulation increases neurite outgrowth in vitro.”
The citation lists haven’t been fetched yet
References 232 · Cited by 221
Research works printed but not linked: 1
- Denhardt D. T. (1999). “Signal transduction pathways and regulation of the mammalian cell cycle: cell type-dependent integration of external signals,” in The Molecular Basis of Cell Cycle and Growth Control ed. Stein G. S. (New York: Wiley-Liss) 225– 304
- Authors
- Money, K. M., & Stanwood, G. D.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Stanwood, Gregg D.
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 7
- Pages
- 260-260
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC3867667
- OpenAlex
- W1987492515
- Semantic Scholar
- 973eb500b1acaac9dd18de2a68986fea91deae47
- Cited by
- 221
- References
- 232
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 22 · 2023: 19 · 2022: 19 · 2021: 15 · 2020: 20 · 2019: 11 · 2018: 21 · 2017: 15 · 2016: 16 · 2015: 14 · 2014: 18
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Vanderbilt University
- National Institute of Mental Health (R01MH086629)
- National Institute of General Medical Sciences (T32GM007347)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD015052)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopamine, brain development, dopamine receptors, neuronal migration, dendritic growth, striatum, frontal cortex, neuropsychiatric disorders, brain circuits, synaptogenesis
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
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