Rethinking schizophrenia in the context of normal neurodevelopment

In the rhesus macaque, the authors found approximately 50,000-80,000 dividing cells per 12 h along the SVZ of juvenile and adult macaques using BrdU and Ki67 positive cell markers of cell proliferation.

“In the rhesus macaque, we have found ~50,000–80,000 dividing cells/12 h along the SVZ of juvenile and adult macaques, using both BrdU and Ki67 positive cell markers of cell proliferation (unpublished; Shalaev et al., 2002).”

The authors observed increasing mRNA expression of MBP, MOBP and PLP1 during the first decade of life, all p < 0.001.

“We observed increasing mRNA expression of MBP, myelin-associated oligodendrocyte basic protein (MOBP) and proteolipid protein 1 (PLP1) during the first decade of life (all p < 0.001).”

• AssumptionRests on an assumption: Post-mortem molecular and histological measures in human brain accurately reflect normal developmental trajectories in vivo.

Post-mortem microarray data from the authors' laboratory demonstrated dramatic increases in mRNA transcripts of myelin proteins in the prefrontal cortex across human post-natal life.

“Post-mortem microarray data from our laboratory (Harris et al., 2009; Weickert et al., 2009), have demonstrated dramatic increases in mRNA transcripts of myelin proteins in the prefrontal cortex across human post-natal life.”

• cites Harris et al., 2009Not checked yet

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• cites Weickert et al., 2009Not checked yet

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• AssumptionRests on an assumption: Post-mortem molecular and histological measures in human brain accurately reflect normal developmental trajectories in vivo.

The authors have found that a variety of synaptic mRNAs and proteins increase steadily after birth during childhood years.

“We have found that a variety of synaptic mRNAs and proteins increase steadily after birth during childhood years (Webster et al., 2011).”

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The authors' recent data from multiple molecular markers suggest that developmental increases in synaptic proteins are not followed by a significant decline either in childhood or in adolescence as would be expected with major synaptic regression.

“Our recent data from multiple molecular markers suggest that developmental increases in synaptic proteins are not followed by a significant decline either in childhood or in adolescence as would be expected with major synaptic regression (Webster et al., 2011).”

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Adult NR2D mRNA decreased to 50% of neonatal levels in the authors' microarray study.

“Adult NR2D mRNA decreased to 50% of neonatal levels in our microarray study (Choi et al., 2009).”

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In DLPFC, GAD65 mRNA peaks around one year of age and stays consistently expressed from infants to adulthood with little or no drop-off.

“However, in the DLPFC, our unpublished microarray data as well as that from Kang et al. (2011) show the mRNA for GAD65 peaks around one year of age and stays consistently expressed from infants to adulthood with little or no drop-off.”

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In schizophrenia patients, NR1 and NR2C mRNA subunit expressions are decreased.

“Our study also described decreased expressions of the NR1 and NR2C mRNA subunits in schizophrenia patients (Weickert et al., 2012), which are consistent with an earlier study (Beneyto and Meador-Woodruff, 2008).”

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• cites Beneyto and Meador-Woodruff, 2008Not checked yet

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In schizophrenia patients, NR1 protein is robustly decreased in prefrontal cortex.

“We recently demonstrated for the first time a robust decrease in NR1 protein in schizophrenia patients in prefrontal cortex (Weickert et al., 2012).”

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In DLPFC, GAD67 mRNA shows a similar pattern to GAD65.

“Our microarray data shows a similar pattern for GAD67”

Developmental disruption well after birth may also contribute to onset of schizophrenia.

“we suggest that developmental disruption well after birth may also contribute to onset of schizophrenia.”

The development of complex executive functions is characterized by a protracted development well through adolescence.

“the development of complex executive functions are characterized by a protracted development well through adolescence (Levin et al., 1991; Anderson et al., 2001; Brocki and Bohlin, 2004).”

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• cites Anderson et al., 2001Not checked yet

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• cites Brocki and Bohlin, 2004Not checked yet

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Feinberg's over-exuberant synaptic pruning theory of schizophrenia is potentially flawed because it relies on the timing of normative synaptic pruning with inaccurately extrapolated synaptic densities that do not appear consistent with more recent studies.

“While we suggest that Feinberg's over-exuberant synaptic pruning theory of schizophrenia is potentially flawed, as it relies on the timing of normative synaptic pruning with inaccurately extrapolated synaptic densities that do not appear consistent with more recent studies”

Human neurodevelopment is not confined to the womb but is a protracted process that continues in post-natal life well into adolescence and early adulthood.

“current data indicate human neurodevelopment is not confined to the womb, but is a protracted process that continues in post-natal life well into adolescence and early adulthood.”

Molecular and cellular maturation in circuitry controlling the magnitude, extent and co-ordination of pyramidal neuron firing across association areas would be expected to increase during childhood and attain near adult levels during adolescence.

“This suggests that molecular and cellular maturation in circuitry controlling the magnitude, extent and co-ordination of pyramidal neuron firing across association areas would be expected to increase during childhood and attain near adult levels during adolescence.”

The protracted development of mature cognition has been linked to relatively late maturation of several association cortices, as compared to other cortical regions such as the sensorimotor and occipital lobes.

“The protracted development of mature cognition has been linked to relatively late maturation of several association cortices, as compared to other cortical regions such as the sensorimotor and occipital lobes (Giedd et al., 1999; Casey et al., 2000; Gogtay et al., 2004; Blakemore and Choudhury, 2006).”

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• cites Casey et al., 2000Not checked yet

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• cites Gogtay et al., 2004Not checked yet

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During difficult reasoning problems, the timing and maintenance of activity increases as performance increases from early childhood to young adulthood.

“Thus, during difficult reasoning problems the timing and maintenance of activity increases as performance increases from early childhood to young adulthood.”

Mature ability to meet executive challenges of the adult is associated with more efficient prefrontal cortical activity.

“Mature ability to meet executive challenges of the adult are associated with more efficient prefrontal cortical activity (Casey et al., 1997; Bunge et al., 2002; Tamm et al., 2002; Durston et al., 2006).”

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• cites Bunge et al., 2002Not checked yet

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• cites Tamm et al., 2002Not checked yet

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The most consistent findings in cognitive dysfunction in schizophrenia are within the domains of executive function, working memory, inhibitory control, and reasoning.

“In terms of cognitive dysfunction, the most consistent findings are within the domains of executive function, working memory, inhibitory control, and reasoning (Weinberger et al., 1986; Goldman-Rakic, 1994; Weickert et al., 2000a; Silver et al., 2003; Ravizza et al., 2010).”

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• cites Goldman-Rakic, 1994Not checked yet

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• cites Weickert et al., 2000aNot checked yet

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During difficult reasoning problems, rostral prefrontal cortical activity is delayed or fails to be sustained in children.

“During difficult reasoning problems rostral prefrontal cortical activity is delayed or fails to be sustained in children (Bunge et al., 2009; Crone et al., 2009).”

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• cites Crone et al., 2009Not checked yet

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The Wisconsin Card Sorting test shows a developmental pattern of gradual performance improvement interspersed with periods of accelerated improvement throughout childhood to young adulthood.

“The Wisconsin Card Sorting test, a classic test of cognitive flexibility and control, which also relies on fronto-parietal function, shows a developmental pattern of gradual performance improvement interspersed with periods of accelerated improvement throughout childhood to young adulthood (Heaton et al., 1993; Figure 1).”

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EEG data show age-related changes in neural oscillations and synchrony that support enhanced temporal coordination of distributed cortical processes throughout development.

“Electroencephalography (EEG) data show age-related changes in neural oscillations and synchrony that support enhanced temporal coordination of distributed cortical processes throughout development (Uhlhaas et al., 2009; Figure 1).”

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The prefrontal cortex is ideally suited to coordinating activity within the neural network to facilitate increased neural efficiency and improved executive function, based on its rich connections with other cortical and subcortical structures.

“In general, based on its rich connections with other cortical and subcortical structures, the prefrontal cortex is also ideally suited to the task of coordinating activity within the neural network to facilitate increased neural efficiency and improved executive function.”

There is a period of destabilization during adolescence, followed by reorganization during young adulthood (18-21 years of age), characterized by increases in gamma-band power, theta and beta band synchrony.

“Interestingly, this work also suggests a period of destabilization during adolescence, followed by reorganization during young adulthood (18–21 years of age), which is characterized by increases in gamma-band power, theta and beta band synchrony.”

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Abnormal patterns of oscillatory brain activity, especially in the gamma range, are observed in patients with schizophrenia.

“abnormal patterns of oscillatory brain activity, especially in the gamma range, are observed in patients (Uhlhaas et al., 2008).”

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Some premorbid individuals displayed lower cognitive ability during childhood and adolescence.

“Population and birth cohort studies show that some premorbid individuals displayed lower cognitive ability during childhood and adolescence.”

Adolescence is a critical window for the organization and functional adjustment of cortical circuitry, rendering this time of life particularly sensitive to disruptive effects.

“Thus, adolescence is a critical window for the organization and functional adjustment of cortical circuitry rendering this time of life particularly sensitive to disruptive effects.”

Other brain regions activated during working memory tasks in children, such as the ventromedial prefrontal cortex, show decreased activity in adolescence and early adulthood during working memory tests.

“Conversely, other brain regions that are activated during working memory tasks in children, such as the ventromedial prefrontal cortex, show decreased activity in adolescence and early adulthood during working memory tests (Scherf et al., 2006).”

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Children and adolescents display less dorsal anterior cingulate activity during performance monitoring compared to adults.

“Similar to under activation of the dorsal frontal cortical regions in working memory performance, children and adolescents display less dorsal anterior cingulate activity during performance monitoring (Velanova et al., 2008).”

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Physiological changes parallel the patterns found for cognitive development where gradual change can be interspersed with brief periods of accelerated cognitive development.

“These physiological changes parallel the patterns found for cognitive development where gradual change can be interspersed with brief periods of accelerated cognitive development (Thatcher, 1991, 1992, 1994).”

• cites Thatcher, 1991, 1992, 1994Not checked yet

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A failure in maturational processes of cognitive executive processes and neural circuitry may play a critical role in the pathophysiology of schizophrenia.

“The concomitant refinement of cognitive executive processes, the physical maturation of neural circuitry underlying executive function, and the onset of schizophrenia in adolescence or early adulthood suggests that a failure in these maturational processes may play a critical role in the pathophysiology of schizophrenia.”

• AssumptionRests on an assumption: Schizophrenia typically has its onset during late adolescence or early adulthood.
• AssumptionRests on an assumption: Schizophrenia onset is coincident in time with cognitive maturation of the prefrontal and parietal cortices.

For some tasks such as those requiring response inhibition, the lateral prefrontal cortex may show decreased activity as development progresses from children to young adults, reflecting increased neural efficiency.

“However, while increased activity in frontal-parietal regions is a general rule throughout development from child to adulthood, for some tasks such as those requiring response inhibition, the lateral prefrontal cortex may show decreased activity (reflecting increased neural efficiency) as development progresses from children to young adults (Fair et al., 2007).”

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Most executive cognitive processes involve the ability to achieve and maintain activation of focal frontal regions in appropriate contexts.

“It is clear from these three examples of cognitive functional change during human development that most executive cognitive processes involve the ability to achieve and maintain activation of focal frontal regions in appropriate contexts.”

A deficit in GABAergic inhibition is one of the most robust findings in schizophrenia neuropathology.

“Indeed, a deficit in GABAergic inhibition is one of the most robust findings in schizophrenia neuropathology, so the timing of cortical interneuron development warrants further consideration.”

There is a period of later development (e.g., adolescence) when neural perturbations may result in schizophrenia.

“The findings described above suggest a period of later development (e.g., adolescence) when neural perturbations may result in schizophrenia.”

Aberrations in neurogenesis and migration processes could be contributing to adolescent-onset neurodevelopmental disorders such as schizophrenia.

“This has implications for adolescent-onset neurodevelopmental disorders, such as schizophrenia, as aberrations in these processes could be contributing to disease.”

In mice lacking normal reelin function (reeler mice), inverted neocortical layers and abnormally dispersed cells are observed due to lack of neuronal ability to respond to migration signals.

“In mice lacking normal reelin function (reeler mice), inverted neocortical layers and abnormally dispersed cells are observed due to lack of neuronal ability to respond to migration signals in reeler mutants (Caviness, 1976; Goffinet, 1984; D'Arcangelo et al., 1995; Chai et al., 2009).”

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• cites Goffinet, 1984Not checked yet

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• cites D'Arcangelo et al., 1995Not checked yet

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Once radial migration of pyramidal neurons ceases, cortical maturation in the form of proper alignment of neuronal cells, synapse formation, and neurite outgrowth lasts from the sixteenth fetal week until the post-natal period.

“Once radial migration of pyramidal neurons ceases, cortical maturation in the form of proper alignment of neuronal cells, synapse formation, and neurite outgrowth lasts from the sixteenth fetal week until the post-natal period (Sidman and Rakic, 1973; Lequin and Barkovich, 1999).”

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• cites Lequin and Barkovich, 1999Not checked yet

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The fact that cortical layering appears to be fairly intact in most cortical areas in schizophrenia is not consistent with a major loss of function of the reelin gene early in development.

“However, the fact that cortical layering appears to be fairly intact in most cortical areas in schizophrenia, is not consistent with a major loss of function of the reelin gene early in development.”

• AssumptionRests on an assumption: Cortical layering appears to be fairly intact in most cortical areas in schizophrenia.

Neurogenesis and the subsequent migration of neurons to the cortex begin within a few weeks of gestation in the human.

“Neurogenesis and the subsequent migration of neurons to the cortex begin within a few weeks of gestation in the human (Zecevic et al., 2011).”

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Neuronal precursors residing in the ventral subventricular zone retain the ability to divide and generate neurons well into post-natal human life and into adulthood.

“However, neuronal precursors residing in the ventral subventricular zone (vSVZ: Haubensak et al., 2004) retain the ability to divide and generate neurons well into post-natal human life and into adulthood (see below)”

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The ventral neurogenic zone gives rise to most of the cortical inhibitory neurons that migrate tangentially to reach the cortex.

“The ventral neurogenic zone gives rise to most of the cortical inhibitory neurons (Anderson et al., 1997; Tamamaki et al., 1997; Ayala et al., 2007) that migrate tangentially to reach the cortex (see below).”

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• cites Tamamaki et al., 1997Not checked yet

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• cites Ayala et al., 2007Not checked yet

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For some neuronal subtypes, neurogenesis and migration may be ongoing throughout development and into adulthood.

“Relatively recent studies challenge dogma by suggesting that for some neuronal subtypes these processes may be ongoing throughout development and into adulthood (Gould et al., 1999; Weickert et al., 2000b; Bernier et al., 2002; Fung et al., 2010, 2011a; Wang et al., 2011).”

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• cites Weickert et al., 2000bNot checked yet

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• cites Bernier et al., 2002Not checked yet

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Prefrontal myelination occurs predominantly in early post-natal life, still increasing through adolescence before reaching adult levels.

“Prefrontal myelination occurs predominantly in early post-natal life, still increasing through adolescence before reaching adult levels (Kang et al., 2011).”

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The greatly expanded neuronal number and surface area of the human cerebral cortex depends on repeated rounds of symmetric cell division followed by later asymmetric division resulting in committed neuronal precursors.

“The greatly expanded neuronal number and surface area of the human cerebral cortex depends on repeated rounds of symmetric cell division followed by later asymmetric division resulting in committed neuronal precursors.”

Proliferation of the calretinin positive cell can be detected in the human dorsal SVZ at 20 gw.

“Proliferation of the calretinin positive cell can be detected in the human dorsal SVZ at 20 gw (Zecevic et al., 2011).”

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Disruption of the vSVZ neurogenesis process would be consistent with the pathology of mental illnesses involving GABAergic interneurons and with a post-natal age of onset, like what is found in schizophrenia.

“Therefore, disruption of the vSVZ neurogenesis process would be consistent with the pathology of mental illnesses involving GABAergic interneurons and with a post-natal age of onset, like what is found in schizophrenia.”

Some of these early processes are not completely exhausted in post-natal life.

“Thus, while we begin with early events, we suggest that some of these early processes are not completely exhausted in post-natal life.”

More selective disruption of the processes controlling vSVZ neurogenesis could lead to much more subtle changes impacting development of cortical interneurons.

“more selective disruption of the processes controlling vSVZ neurogenesis could lead to much more subtle changes impacting development of cortical interneurons.”

Structural brain changes present in adolescence or young adults during the early transition to illness provide further support for the view that brain changes in schizophrenia are prominent in prefrontal and associative cortical regions.

“Structural brain changes present in adolescence or young adults during the early transition to illness provide further support for this view (Pantelis et al., 2003).”

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Neurogenesis has been implicated in schizophrenia pathology by the involvement of disease-associated neurogenesis regulator genes such as DISC1 and neuregulin.

“Neurogenesis has been implicated in schizophrenia pathology by the involvement of disease-associated neurogenesis regulator genes such as DISC1 and neuregulin (Millar et al., 2000; Ghashghaei et al., 2006; Duan et al., 2007; Mao et al., 2009).”

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• cites Ghashghaei et al., 2006Not checked yet

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• cites Duan et al., 2007Not checked yet

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There may be at least two different patterns of cognitive decline in people who are destined to develop schizophrenia.

“We suggest that there may be at least two different patterns of cognitive decline in people who are destined to develop schizophrenia.”

The dorsal (pallium) and ventral (subpallium) neurogenic zones by and large give rise to the two different neuronal types of the cortex.

“One of the most important divisions of the telencephalon relevant to schizophrenia neuropathology is the distinction between the dorsal (pallium) and ventral (subpallium) neurogenic zones as they by and large give rise to the two different neuronal types of the cortex.”

Given that there are not gross abnormalities in the size or shape of the human brain in most cases of schizophrenia, it is likely that very early embryonic events of division and early neuronal differentiation are intact in most people who later go on to develop schizophrenia.

“Given that there are not gross abnormalities in the size or shape of the human brain (in most cases of schizophrenia) it is likely that these very early embryonic events of division and early neuronal differentiation are intact in most people who later go on to develop schizophrenia.”

• AssumptionRests on an assumption: There are not gross abnormalities in the size or shape of the human brain in most cases of schizophrenia.

One pattern of cognitive decline in people destined to develop schizophrenia is found early in life with widespread intellectual impairment, implying that early developmental processes occurring before 8 years of age may have gone awry.

“One pattern where cognitive decline is found early in life and intellectual impairment is widespread, implying that early developmental processes occurring before 8 years of age may have gone awry (Weickert and Goldberg, 2000).”

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Adolescent cognitive development in particular is subject to perturbation in at least 40% of men and women later diagnosed with schizophrenia.

“there is evidence showing that it is adolescent cognitive development in particular that is subject to perturbation in at least 40% of men and women later diagnosed with schizophrenia (Reichenberg et al., 2005).”

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Radial migration, via radial glial cells, occurring around 20 gw in humans, is the main mode of migration for pyramidal neurons.

“Radial migration, via radial glial cells, occurring around 20 gw in humans, is the main mode of migration for pyramidal neurons (Rakic, 1972; Nadarajah et al., 2001; Hatten, 2002; Nadarajah and Parnavelas, 2002; Nadarajah, 2003; Figure 2).”

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• cites Nadarajah et al., 2001Not checked yet

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• cites Hatten, 2002Not checked yet

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Ample evidence exists for increased interstitial white matter neuron densities in schizophrenia.

“Ample evidence for increased interstitial white matter neuron (IWMN) densities in schizophrenia exists (Akbarian et al., 1993; Anderson et al., 1996; Eastwood and Harrison, 2003, 2005a; Kirkpatrick et al., 2003; Yang et al., 2011; Joshi et al., 2012).”

• cites Akbarian et al., 1993Not checked yet

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• cites Anderson et al., 1996Not checked yet

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• cites Eastwood and Harrison, 2003, 2005aNot checked yet

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Recruitment, differentiation, growth, and refinement of cortical inhibitory interneurons is a major developmental event, if not the major developmental event, occurring as cognitive abilities like working memory and language are initially attained.

“Taken together, these results suggest that recruitment, differentiation, growth, and refinement of cortical inhibitory interneurons is a major developmental event, if not the major developmental event, occurring as cognitive abilities like working memory and language are initially attained.”

The cell density or mRNA expression of other interneuron markers, such as calbindin and vasoactive intestinal peptide, increase in the early post-natal years reaching a peak in children (~4-7 in human) prior to declining to adult levels in adolescence.

“The cell density or mRNA expression of other interneuron markers, such as calbindin and vasoactive intestinal peptide increase similarly in the early post-natal years reaching a peak in children (~4–7 in human) prior to declining to adult levels in adolescence (Yan et al., 1995; Delalle et al., 1997; Fung et al., 2010; Figure 3).”

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• cites Delalle et al., 1997Not checked yet

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• cites Fung et al., 2010Not checked yet

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A recent study by Alvarez-Buylla and colleagues provides further evidence of a major migratory pathway of DCX+, PSA-NCAM+ cells in post-natal human brains originating from the SVZ and targeting prefrontal cortex.

“A recent study by Alvarez-Buylla and colleagues (Sanai et al., 2011) provides further evidence of a major migratory pathway (DCX+, PSA-NCAM+ cells) in post-natal human brains originating from the SVZ and targeting prefrontal cortex.”

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The peak in the ratio of GABA α1 to α2 subunits coincides with increased gamma band power in the prefrontal cortex.

“The peak in the ratio of GABA α1 to α2 subunits (GABRA1/GABRA2) coincides with increased gamma band power in the prefrontal cortex (refer Figure 1).”

Normal development of GABA receptor components of the inhibitory system is dynamic until adolescence, when the trajectories reach a steady or declining state.

“Normal development of GABA receptor components of the inhibitory system is dynamic until adolescence where the trajectories reach a steady or declining state.”

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Other studies have demonstrated BrdU and NeuN/GAD67 co-labeled cells in the principal sulcus of adult macaques, suggesting that some dividing cells may contribute to an adult generated population of interneurons in the cortex.

“Other studies have demonstrated BrdU and NeuN/GAD67 co-labeled cells in the principal sulcus of adult macaques (Gould et al., 1999; Koketsu et al., 2003; Runyan et al., 2006; Ashrafi et al., 2007) suggesting that some of these dividing cells may contribute to an adult generated population of interneurons in the cortex.”

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• cites Koketsu et al., 2003Not checked yet

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• cites Runyan et al., 2006Not checked yet

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The presence of GAD65/67+, somatostatin+ and neuropeptide Y+ neurons with morphology reminiscent of tangentially migrating cells in post-natal white matter of primates may indicate the presence of post-natally migrating interneurons.

“Additionally, the presence of GAD65/67+, somatostatin+ and neuropeptide Y+ neurons with morphology reminiscent of tangentially migrating cells (elongated cell body and leading and/or trailing processes parallel to the pial surface) in the post-natal white matter of primates may indicate the presence of post-natally migrating interneurons (Fung et al., 2011a; Yang et al., 2011; Joshi et al., 2012).”

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• cites Yang et al., 2011Not checked yet

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• cites Joshi et al., 2012Not checked yet

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Parvalbumin and cholecystokinin mRNAs are increased over post-natal development in humans, most strikingly in the first 5 post-natal years.

“Measurement of biochemical markers representing different interneuron subtypes suggests that parvalbumin and cholecystokinin mRNAs are increased over post-natal development in humans, most strikingly in the first 5 post-natal years (Figure 3).”

During development of the mammalian telencephalon, interneurons migrate tangentially from the ventral ganglionic eminences (vSVZ) to the developing cortex.

“During development of the mammalian telencephalon, interneurons migrate tangentially from the ventral ganglionic eminences (vSVZ) to the developing cortex (Corbin et al., 2001; Marin and Rubenstein, 2003; Takemura, 2005).”

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• cites Marin and Rubenstein, 2003Not checked yet

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• cites Takemura, 2005Not checked yet

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Myelination is another developmental event that extends well into post-natal life.

“Another developmental event that extends well into post-natal life is myelination (Figure 2).”

In primates, there are several reports of immature neurons in the amygdala, and in piriform, inferior temporal and prefrontal cortices in post-natal life.

“In primates, there are several reports of immature neurons in the amygdala, and in piriform, inferior temporal and prefrontal cortices in post-natal life (Gould et al., 1999, 2001; Bernier et al., 2002; Runyan et al., 2006; Ashrafi et al., 2007).”

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• cites Bernier et al., 2002Not checked yet

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• cites Runyan et al., 2006Not checked yet

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Brain axonal tracts are myelinated progressively across the lifespan in a region- and function-specific manner.

“Brain axonal tracts are myelinated progressively across the lifespan in a region- and function-specific manner.”

High levels of neuronal migration markers DCX and PSA-NCAM in infants provide compelling evidence that cortical interneuron migration continues post-natally, particularly in the first few years of life.

“high levels of neuronal migration markers such as DCX and poly-sialyated neuronal cell adhesion molecule (PSA-NCAM) in infants (Cox et al., 2009; Fung et al., 2011a; Kang et al., 2011; Xu et al., 2011) provide compelling evidence that cortical interneuron migration continues post-natally, particularly in the first few years of life”

• cites Cox et al., 2009Not checked yet

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• cites Fung et al., 2011aNot checked yet

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• cites Kang et al., 2011Not checked yet

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Observations of increased subcortical neurons in schizophrenia can also be interpreted as due to abnormal tangential migration of cortical inhibitory interneurons from the vSVZ.

“However, the observations of increased subcortical neurons found in schizophrenia can also be interpreted as being due to abnormal tangential migration of cortical inhibitory interneurons from the vSVZ (Yang et al., 2011; Joshi et al., 2012; Volk et al., 2012).”

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• cites Joshi et al., 2012Not checked yet

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• cites Volk et al., 2012Not checked yet

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A comprehensive larger study graded myelination in 62 white matter sites within 162 post-mortem brains from newborn to 3 years of age.

“A comprehensive larger study graded myelination in 62 white matter sites within 162 post-mortem brains from newborn to 3-years of age (Brody et al., 1987; Kinney et al., 1988).”

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• cites Kinney et al., 1988Not checked yet

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Addition of new cortical interneurons may contribute to the large growth of the human brain evidenced by a quadrupling of brain weight and a large increase in cortical gray matter volume from birth to about 5 years of age.

“Since we and others find a high density of nascent neurons in their birthplace, the SVZ, and a high neuronal density just below the cortex in human infants (Chong et al., 2008; Fung et al., 2011a; Wang et al., 2011), this suggest that addition of new cortical interneurons may contribute to the large growth of the human brain evidenced by a quadrupling of brain weight (Dekaban and Sadowsky, 1978;”

• cites Chong et al., 2008Not checked yet

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• cites Fung et al., 2011aNot checked yet

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• cites Wang et al., 2011Not checked yet

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There is strong evidence for reduced expression of parvalbumin and somatostatin in schizophrenia.

“Specifically, there is strong evidence for reduced expression of the calcium binding protein parvalbumin (Beasley and Reynolds, 1997; Reynolds and Beasley, 2001; Reynolds et al., 2002; Hashimoto et al., 2008a,b; Morris et al., 2008; Sakai et al., 2008; Bitanihirwe et al., 2009; Mellios et al., 2009; Fung et al., 2010) and the neuromodulatory peptide, somatostatin (Hashimoto et al., 2008a,b; Morris”

• cites Beasley and Reynolds, 1997Not checked yet

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• cites Hashimoto et al., 2008a,bNot checked yet

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• cites Fung et al., 2010Not checked yet

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By 11 years of age, myelinated fiber density in the hippocampus was well developed but had not reached the highest adult levels.

“By 11 years of age, myelinated fiber density in the hippocampus was well developed but had still not reached the highest adult levels (Abraham et al., 2010).”

• cites Abraham et al., 2010Not checked yet

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Deficits of working memory are consistently seen in schizophrenia.

“Deficits of working memory are also consistently seen in schizophrenia (Goldman-Rakic, 1994; Meyer-Lindenberg et al., 2005)”

• cites Goldman-Rakic, 1994Not checked yet

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• cites Meyer-Lindenberg et al., 2005Not checked yet

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Basilar dendritic complexity appeared greater in younger individuals aged 14-40 years than in older individuals aged 40-106 years.

“In another study, basilar dendritic complexity appeared greater in younger individuals (14–40 years of age) than in older individuals (40–106 years of age; Jacobs et al., 1997).”

• cites Jacobs et al., 1997Not checked yet

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Structural abnormalities in white matter underlying the DLPFC have been reported in schizophrenia.

“and structural abnormalities in white matter underlying the DLPFC have also been reported (Kyriakopoulos et al., 2008).”

• cites Kyriakopoulos et al., 2008Not checked yet

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The dendritic segment count reached adult levels by the age of 12 months.

“The dendritic segment count reached adult levels by the age of 12 months.”

• cites Petanjek et al., 2008Not checked yet

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Microarray studies of post-mortem brains from patients with schizophrenia have implicated myelination deficits in the pathology of schizophrenia.

“Microarray studies of post-mortem brains from patients with schizophrenia have implicated myelination deficits in the pathology of schizophrenia (Hakak et al., 2001; Matthews et al., 2012).”

• cites Hakak et al., 2001Not checked yet

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• cites Matthews et al., 2012Not checked yet

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A 3-fold increase in the length of the dendritic tree of layer III pyramidal cells by 2.5 months of age with an additional 50% increase in the length of terminal dendritic segments between 16 and 30 months of age was observed.

“A 3-fold increase in the length of the dendritic tree of layer III pyramidal cells by 2.5 months of age with an additional 50% increase in the length of terminal dendritic segments between 16 and 30 months of age was observed.”

• cites Petanjek et al., 2008Not checked yet

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Quantification of Golgi-impregnated tissue suggests an increase in spine density from birth until early school age, followed by a period of gradually decreasing density starting in early adulthood which lasts until middle age.

“Quantification of Golgi-impregnated tissue suggests an increase in spine density from birth until early school age, followed by a period of gradually decreasing density starting in early adulthood which lasts until middle age (Petanjek et al., 2011).”

• cites Petanjek et al., 2011Not checked yet

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In numerous regions, including prefrontal regions, myelination continues throughout the second decade of life with full maturation only reached in late adolescence or young adulthood.

“However, in numerous regions, including prefrontal regions, the process continues throughout the second decade of life with full maturation only reached in late adolescence or young adulthood.”

Targeted investigations of cortex have revealed a decrease in mRNA and protein levels of MBP in schizophrenia, though not consistently.

“These observations have been validated by targeted investigations of cortex, which have revealed a decrease in mRNA (Matthews et al., 2012) and protein levels (Honer et al., 1999; Parlapani et al., 2009) of MBP in schizophrenia, though not consistently”

• cites Matthews et al., 2012Not checked yet

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• cites Honer et al., 1999Not checked yet

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• cites Parlapani et al., 2009Not checked yet

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A subsequent report with four adolescent cases could suggest that there may be no change or a small net increase in synapse density between infancy and adolescence in the human prefrontal cortex.

“A subsequent report by Huttenlocher and Dabholkar (1997) with four adolescent cases could suggest in fact that there may indeed be no change or a small net increase in synapse density in the time period between infancy and adolescence in the human prefrontal cortex.”

• cites Huttenlocher and Dabholkar, 1997Not checked yet

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Overall, the studies provide strong evidence that myelination throughout the brain takes place most rapidly early in life.

“Overall, these studies provide strong evidence that myelination throughout the brain takes place most rapidly early in life.”

After the first year of life, and throughout childhood and adolescence, changes in white matter fractional anisotropy are more subtle and are predominantly due to altered perpendicular diffusivity, reflecting increasing myelination.

“After the first year of life, and throughout childhood and adolescence, changes in white matter measures (fractional anisotropy) are more subtle and are predominantly due to altered perpendicular diffusivity, reflecting increasing myelination (Giorgio et al., 2008; Lebel et al., 2008; Gao et al., 2009).”

• cites Giorgio et al., 2008Not checked yet

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• cites Lebel et al., 2008Not checked yet

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• cites Gao et al., 2009Not checked yet

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In brain regions implicated in schizophrenia, such as the prefrontal cortex, full white matter maturation is mostly achieved prior to the period of life when schizophrenia emerges.

“In brain regions implicated in the pathogenesis of schizophrenia, such as the prefrontal cortex, full white matter maturation is mostly achieved prior to the period of life when schizophrenia emerges.”

• AssumptionRests on an assumption: Schizophrenia onset typically occurs during adolescence or early adulthood.

A plateau in intermediate dendritic segment length was observed during late adolescence, a period represented by three cases in the study.

“A plateau in intermediate dendritic segment length was observed during late adolescence, a period which was represented by three cases in this study (Figure 4).”

• cites Petanjek et al., 2008Not checked yet

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Other recent microarray data show that expression of genes associated with myelination reached approximately 50% of adult levels by birth and 95% of adult levels by 2-3 years of age in the neocortex.

“These findings are supported by other recent microarray data, in which expression of genes associated with myelination reached approximately 50% of adult levels by birth and 95% of adult levels by 2–3 years of age in the neocortex (Kang et al., 2011).”

• cites Kang et al., 2011Not checked yet

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Considering that basilar dendrites occupy an estimated 60% of total dendritic length, the reported loss of dendrites still may be only a partial explanation for cortical volume loss.

“Considering that basilar dendrites occupy an estimated 60% of the total dendritic length (Soloway et al., 2002), this reported loss of dendrites still may be only a partial explanation for cortical volume loss.”

• cites Soloway et al., 2002Not checked yet

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It is premature to consider all gray matter reduction in schizophrenia to be due solely to loss of synapses or to over-exuberant synaptic pruning.

“We suggest that it is premature to consider all gray matter reduction in schizophrenia to be due solely to loss of synapses or to over-exuberant synaptic pruning.”

This position gains additional support from the lack of consistent molecular changes in presynaptic mRNAs and proteins in schizophrenia brains.

“This position gains additional support from the lack of consistent molecular changes in presynaptic mRNAs and proteins in schizophrenia brains (see below).”

Overall there is a major developmental increase in synaptic components, especially at the protein level, from neonates through school age and adolescence that remains relatively stable through adolescence and into adulthood.

“Overall there is a major developmental increase in synaptic components, especially at the protein level, from neonates through school age and adolescence that remains relatively stable through adolescence and into adulthood.”

The work reviewed provides evidence that the theory stating that exuberant excitatory synapse loss could be the basis for aberrant adolescent brain development in schizophrenia may need to be reconsidered.

“The work reviewed here provides evidence that the theory stating that exuberant excitatory synapse loss could be the basis for the aberrant adolescent brain development in schizophrenia may need to be reconsidered.”

Salimi et al. found a similar pattern of a late peak in the protein expression of complexin 2, a marker of excitatory synapses.

“Consistent with this, Salimi et al. (2008) found a similar pattern of a late peak in the protein expression of complexin 2, a marker of excitatory synapses.”

• cites Salimi et al., 2008Not checked yet

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These observations are contradictory to the model proposed by earlier studies that suggested the major developmental event in adolescence is regression or loss of synaptic elements.

“These observations are contradictory to the model proposed by earlier studies that suggested the major developmental event in adolescence is regression or loss of synaptic elements (Huttenlocher, 1979; Feinberg, 1983; Glantz et al., 2007).”

• cites Huttenlocher, 1979Not checked yet

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• cites Feinberg, 1983Not checked yet

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• cites Glantz et al., 2007Not checked yet

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The most substantial change observed was in dendritic spine measures, with a gradual 50% decrease in the number and density of spines from the mid-twenties to mid-adulthood at 40 years.

“The most substantial change observed was in dendritic spine measures, with a gradual 50% decrease in the number and density of spines from the mid-twenties to mid-adulthood (40 years: Jacobs et al., 1997).”

• cites Jacobs et al., 1997Not checked yet

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Based on available histological evidence, Bennett suggests that a deficit in spines alone would be insufficient to explain the gray matter loss found in imaging studies, typically an 8-10% reduction.

“Based on available histological evidence from studies on people with schizophrenia, Bennett suggests that a deficit in spines (Glantz and Lewis, 2000; Kolluri et al., 2005) alone would be insufficient to explain the gray matter loss found in imaging studies which is typically on the order of a 8–10% reduction.”

• cites Bennett, 2011Not checked yet

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• cites Glantz and Lewis, 2000Not checked yet

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• cites Kolluri et al., 2005Not checked yet

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The fact that loss of spines is anatomically restricted, occurring in deep layer III but not superficial layer III and not in layers V or VI in frontal cortex, supports that spine loss is likely only a partial explanation for cortical thinning.

“The fact that the loss of spines is quite anatomically restricted, i.e., occurs in deep layer III, but not in superficial layer III, and is not found in layers V or layers VI in frontal cortex also supports that spine loss is likely only a partial explanation for cortical thinning (Glantz and Lewis, 2000; Kolluri et al., 2005).”

• cites Glantz and Lewis, 2000Not checked yet

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• cites Kolluri et al., 2005Not checked yet

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Studies of markers of excitatory synapses in neocortex of patients with schizophrenia primarily find no change or slightly decreased levels.

“Studies of markers of excitatory synapses in neocortex of patients with schizophrenia primarily find no change (Eastwood and Harrison, 2001, 2005b; Sawada et al., 2002; Halim et al., 2003; Fung et al., 2011b) or slightly decreased levels (Eastwood and Harrison, 2005b).”

• cites Eastwood and Harrison, 2001, 2005bNot checked yet

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• cites Sawada et al., 2002Not checked yet

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• cites Halim et al., 2003Not checked yet

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Taken together, schizophrenia in general does not appear to be characterized by a pervasive and consistent loss of excitatory synapse markers.

“Taken together, schizophrenia, in general, does not appear to be characterized by a pervasive and consistent loss of excitatory synapse markers.”

Measurement of excitatory spine markers has led to divergent results mainly suggesting no change or only slight decreased expression of spinophilin and PSD-95 in cortex of patients with schizophrenia.

“Similarly, measurement of excitatory spine markers has led to divergent results (Law et al., 2004; Weickert et al., 2004; Toro and Deakin, 2005; Kristiansen et al., 2006; Catts and Weickert, 2012), mainly suggesting there is no change or only slight decreased expression of spinophilin and PSD-95 in cortex of patients with schizophrenia.”

• cites Law et al., 2004Not checked yet

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• cites Weickert et al., 2004Not checked yet

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• cites Toro and Deakin, 2005Not checked yet

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Henson et al. found that NR1 mRNA and protein levels significantly changed across age in a sample from 18 gestational weeks to 25 years old.

“One of the first studies to examine NR1 mRNA and protein levels across human development in the PFC (Henson et al., 2008) found expression significantly changed across age in a sample from 18 gw to 25-years old.”

• cites Henson et al., 2008Not checked yet

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Schizophrenia pathophysiology likely involves disruptions to three neurotransmitter systems: excitatory glutamatergic, inhibitory GABAergic, and modulating dopaminergic input.

“Schizophrenia pathophysiology likely involves disruptions to three neurotransmitter systems, namely; excitatory glutamatergic, inhibitory GABAergic, and modulating dopaminergic, input [reviewed in Seshadri et al. (2013)]”

• cites Seshadri et al. (2013)Not checked yet

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The reviewed data suggest that the onset of synaptic regression is unlikely to be the trigger for the onset of schizophrenia.

“Thus, the reviewed data suggest that the onset of synaptic regression is unlikely to be the trigger for the onset of schizophrenia.”

• AssumptionRests on an assumption: Schizophrenia onset typically occurs during adolescence or early adulthood.

This suggests that the interpretation of earlier findings of changes in synaptic density reported by Huttenlocher could have been influenced by the many individuals in the 60-80 year range.

“This suggests that the interpretation of earlier findings of changes in synaptic density reported by Huttenlocher (1979) could have been influenced by the many individuals in the 60–80 year range.”

• cites Huttenlocher, 1979Not checked yet

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GABA production enzymes are expressed at a steady rate despite large changes in distribution, maturational state, and phenotype of interneuron populations in post-natal human life.

“This is interesting as the enzymes responsible for GABA production are expressed at a steady rate despite large changes in distribution, maturational state, and phenotype of the interneuron populations that occur in post-natal human life”

mRNA for both constitutive and synaptic synthesis of GABA is fairly stable throughout post-natal life.

“implying that mRNA for both constitutive and synaptic synthesis of GABA is fairly stable throughout post-natal life.”

NR1 mRNA expression followed a similar pattern to NR1 protein but with a less marked reduction in adulthood.

“The mRNA expression followed a similar pattern but with a less marked reduction in adulthood.”

• cites Henson et al., 2008Not checked yet

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Two recent transcriptome analyses charted NMDAR subunit mRNAs in human prefrontal cortex from early gestation to old age.

“Two recent transcriptome analyses have also charted NMDAR subunit mRNAs in human prefrontal cortex from early gestation to old age (Colantuoni et al., 2011; Kang et al., 2011; Figure 5).”

• cites Colantuoni et al., 2011Not checked yet

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• cites Kang et al., 2011Not checked yet

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This suggests that the critical period for NMDAR mediated plasticity in humans may start around toddlerhood in the prefrontal cortex, at a time where language acquisition and utilization grows at a rapid pace.

“This suggests that the critical period for NMDAR mediated plasticity in humans may start around toddlerhood in the prefrontal cortex (Wong et al., 2002; Perez-Otano et al., 2006) at a time where language acquisition and utilization grows at a rapid pace.”

• cites Wong et al., 2002Not checked yet

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• cites Perez-Otano et al., 2006Not checked yet

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The decreasing NR2A/NR2B ratio across life may be responsible for the decrease in plasticity seen during maturation and ageing.

“Thus, the decreasing NR2A/NR2B ratio across life may be responsible for the decrease in plasticity seen during maturation and ageing (Crair and Malenka, 1995).”

• cites Crair and Malenka, 1995Not checked yet

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In the developing rodent brain, there is a shift in the ratio of NR2A/NR2B containing receptors during post-natal development in several brain regions, with a higher proportion of NR2A-rich receptors in later life.

“Thus, in the developing rodent brain, there is a shift in the ratio of NR2A/NR2B containing receptors during post-natal development in several brain regions, with a higher proportion of NR2A-rich receptors in later life (Ritter et al., 2002; Turman et al., 2002).”

• cites Ritter et al., 2002Not checked yet

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• cites Turman et al., 2002Not checked yet

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In two recent transcriptome analyses, prenatal expression of all NMDAR subunit mRNAs was low except NR2B mRNA, which is high prenatally and peaks shortly before birth.

“In two recent transcriptome analyses, the prenatal expression of all NMDAR subunit mRNAs were found to be low in both studies, with exception of NR2B mRNA which is high prenatally and peaks shortly before birth (Colantuoni et al., 2011; Kang et al., 2011).”

• cites Colantuoni et al., 2011Not checked yet

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• cites Kang et al., 2011Not checked yet

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In schizophrenia, NR3A mRNA is significantly increased.

“The Meador–Woodruff group also reported a significant increase in NR3A mRNA (Mueller and Meador-Woodruff, 2004)”

• cites Mueller and Meador-Woodruff, 2004Not checked yet

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Taken together, the results suggest that the major post-natal change in human cortical NMDARs may not be the NR2B to NR2A switch, but rather may feature down-regulation of NR2D and NR3A more prominently.

“Taken together, these results suggest that the major post-natal change in human cortical NMDARs may not be the NR2B to NR2A switch, but rather may feature the down-regulation of NR2D and NR3A more prominently.”

Elimination of interneuronal expression of mature NMDARs post-natally, but prior to onset of adolescence, leads to a schizophrenia-like phenotype in mice.

“Elimination of interneuronal expression of mature NMDARs post-natally, but prior to onset of adolescence, leads to a schizophrenia-like phenotype in mice (Belforte et al., 2010)”

• cites Belforte et al., 2010Not checked yet

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Binding studies show mixed results depending on brain region and binding site.

“Binding studies also show mixed results depending on brain region and binding site.”

In the rat hippocampus, the NR2A/NR2B ratio is believed to mediate the process of synaptic remodeling.

“In the rat hippocampus, the NR2A/NR2B ratio is believed to mediate the process of synaptic remodeling (Gambrill and Barria, 2011).”

• cites Gambrill and Barria, 2011Not checked yet

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The reversal from hyperpolarizing to depolarizing GABA is due to high chloride concentrations in immature neurons caused by high developmental expression of NKCC1.

“This reversal is due to the high chloride concentrations found in immature neurons due to high developmental expression of Na-K-Cl co-transporter 1 (NKCC1, also known as SLC12A2: Di Cristo, 2007).”

• cites Di Cristo, 2007Not checked yet

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β2 and γ2 subunit mRNAs do not achieve their peak of expression until teenage/young adult years.

“However, changes in individual receptor subunit mRNAs for the β2, γ2 subunits do not achieve their peak of expression until the teenage/young adult years (Fillman et al., 2010)”

• cites Fillman et al., 2010Not checked yet

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DRD4 expression as determined by in situ hybridization is stable across the lifespan.

“The expression of DRD4 as determined by in situ hybridization is stable across the lifespan (Weickert et al., 2007).”

• cites Weickert et al., 2007Not checked yet

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In DLPFC, human post-natal developmental change in GABAA receptor α/β/γ subunits divides into two groups: decreasing mRNA expression (α2, α5, β1, γ1, γ3) and dynamic M-shape peaking at toddler and teenage periods (α1, α4, β2, β3, γ2).

“In the DLPFC, the human post-natal developmental change in the GABAA receptor α/β/γ subunits can be divided into two groups (Figure 3). The first comprises the subunits with decreasing mRNA expression over the course of development (α2, α5, β1, γ1, γ3) and the second comprises those with a more dynamic expression pattern (α1, α4, β2, β3, γ2) with an M-shape peaking at the toddler and teenage time”

• cites Duncan et al., 2010Not checked yet

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• cites Fillman et al., 2010Not checked yet

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The changes in GABAA subunits in schizophrenia (increase in α2 and decrease in α1) could reflect a cortex held in a state of immaturity into adulthood.

“The changes occurring in GABAA subunits in schizophrenia (an increase in α2 and a decrease α1) could be interpreted to reflect a cortex that may be held in a state of immaturity into adulthood.”

Changes in the ratio of other GABAA receptor subunits may contribute to increasing cognitive capacity of humans through development.

“implying changes in the ratio of other GABAA receptor subunits also may contribute to increasing cognitive capacity of humans through development.”

Consistent reductions in expression of GAD67 are found in schizophrenia.

“Findings include consistent reductions in expression of GAD67, which have been recently reviewed (Gonzalez-Burgos et al., 2010).”

• cites Gonzalez-Burgos et al., 2010Not checked yet

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In DLPFC from schizophrenia patients, GABAA α2 subunit labeled axon initial segments are increased.

“In DLPFC from schizophrenia patients, Volk et al. (2002) found an increase in GABAA α2 subunit labeled axon initial segments.”

• cites Volk et al., 2002Not checked yet

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NKCC1 is highly expressed during early fetal human development and increases until reaching a plateau in early childhood in DLPFC.

“NKCC1 is highly expressed during early fetal human development and increases until reaching a plateau in early childhood in the DLPFC (Hyde et al., 2011).”

• cites Hyde et al., 2011Not checked yet

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Expression of DRD2 (both forms), DRD4, and DRD5 mRNAs displays highest levels in infants and then declines with age.

“The expression of DRD2 (both forms), DRD4, DRD5 mRNAs all display a predominate pattern of developmental change with highest levels of expression in infants that then declines with age (Weickert et al., 2007; Rothmond et al., 2012; Figure 6).”

• cites Weickert et al., 2007Not checked yet

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• cites Rothmond et al., 2012Not checked yet

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There is a replicable change toward an increase in GABA binding in the cortex of people with schizophrenia.

“While there appears to be a replicable change toward an increase in GABA binding in the cortex of people with schizophrenia (Benes et al., 1992; Dean et al., 1999; Newell et al., 2007; Verdurand et al., 2013)”

• cites Benes et al., 1992Not checked yet

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• cites Dean et al., 1999Not checked yet

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• cites Newell et al., 2007Not checked yet

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In adolescent rodents, DRD1 receptors interact with NMDARs on pyramidal neurons to increase the likelihood that they would be driven into "up-states" thought necessary for working memory function.

“Indeed, DRD1 receptors in adolescent rodents were shown to interact with NMDARs on pyramidal neurons to increase the likelihood that they would be driven into “up-states” thought to be necessary for working memory function (Tseng et al., 2007).”

• cites Tseng et al., 2007Not checked yet

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In conditions of high dopamine, this leads to greater contrast between pyramidal neurons firing due to strong excitatory input and suppression of background activity of surrounding pyramidal cells.

“In conditions of high dopamine, this leads to a greater contrast between pyramidal neurons firing due to strong excitatory input and the suppression of background activity of surrounding pyramidal cells (see O'Donnell, 2010 for a review).”

• cites O'Donnell, 2010Not checked yet

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Decreased expression of GABAA subunits α1 and α5 in DLPFC from patients with schizophrenia has been more consistently observed.

“In contrast, decreased expression of the GABAA subunits α1 and α5 in the DLPFC from patients with schizophrenia has been more consistently observed (Hashimoto et al., 2008a; Duncan et al., 2010; Beneyto et al., 2011).”

• cites Hashimoto et al., 2008aNot checked yet

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• cites Duncan et al., 2010Not checked yet

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• cites Beneyto et al., 2011Not checked yet

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Deficits in cortical inhibitory interneurons across several cortical regions, including DLPFC, are among the most robust findings in schizophrenia neuropathology.

“One of the most robust findings in schizophrenia neuropathology is deficits in cortical inhibitory interneurons across several cortical regions (Hashimoto et al., 2008a; Thompson et al., 2009), including DLPFC.”

• cites Hashimoto et al., 2008aNot checked yet

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• cites Thompson et al., 2009Not checked yet

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DRD2 isoforms and DRD5 peak prenatally and show continuous decline in expression throughout life, excepting a small increase in early twenties.

“The DRD2 isoforms and DRD5 show an inverse pattern, peaking prenatally with a continuous decline in expression throughout life, excepting a small increase in the early twenties (Rothmond et al., 2012).”

• cites Rothmond et al., 2012Not checked yet

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DRD1 expression suggests an inverted U-shape with increasing expression until mid-twenties after which there is a slow decline.

“Expression of dopamine receptor, DRD1 suggests an inverted U-shape with increasing expression of receptors until the mid-twenties after which there is a slow decline (Rothmond et al., 2012).”

• cites Rothmond et al., 2012Not checked yet

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Schizophrenia could be considered to result from a failure to reach the final state of cortical maturation, resulting in retainment of an immature cortex (at least transiently), rather than from excess of adolescent synaptic pruning.

“We suggest that, when theorizing about the neurodevelopmental basis of schizophrenia, schizophrenia could be considered to result from a failure to reach the final state of cortical maturation resulting in retainment of an immature cortex (at least transiently) rather than resulting from excess of adolescent synaptic pruning.”

Age of exposure to drugs may interact with normal developmental changes in NMDARs to bring about differential cortical effects and distinct behavioral effects.

“This suggests that age of exposure to drugs may interact with normal developmental changes in NMDARs to bring about differential cortical effects and can result in distinct behavioral effects.”

In humans, cannabinoid CB1 receptor mRNA is highly expressed in DLPFC from birth until toddlerhood, then falls rapidly until adolescence and is reduced to a trough by adulthood.

“In humans, cannabinoid CB1 receptor mRNA is highly expressed in the DLPFC from birth until toddlerhood, when it begins to fall rapidly until adolescence and is reduced to a trough by adulthood (Long et al., 2012; Figure 6).”

• cites Long et al., 2012Not checked yet

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The predominant neurodevelopmental model positing synaptic regression as the dominant feature of adolescence is an overly simplistic and temporally inaccurate way to frame adolescent development of the human cortex.

“We suggest that this view is an overly simplistic and a temporally inaccurate way to frame adolescent development of the human cortex.”

• AssumptionRests on an assumption: The predominant neurodevelopmental model used to underpin the emergence of schizophrenia during adolescence posits synaptic regression as the dominant feature of adolescence.

The majority of CB1 receptors are localized to GABAergic terminals.

“since the majority of CB1 receptors are localized to GABAergic terminals (Eggan et al., 2010a).”

• cites Eggan et al., 2010aNot checked yet

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Behavioral sensitization to stimulant drugs observed in adults can be absent in adolescent rodents.

“Furthermore, the behavioral sensitization to stimulant drugs observed in adults can be absent in adolescent rodents (Laviola et al., 1995; Adriani et al., 1998).”

• cites Laviola et al., 1995Not checked yet

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• cites Adriani et al., 1998Not checked yet

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Perinatal NMDAR antagonist administration induces impairments in attention, working memory, executive function, and social cognition in adulthood.

“Perinatal NMDAR antagonist administration induces impairments in attention, working memory, executive function, and social cognition in adulthood (Du Bois and Huang, 2007).”

• cites Du Bois and Huang, 2007Not checked yet

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It may be inaccurate to consider the major developmental event of the human cortex to be one of synaptic regression.

“Thus, it may be inaccurate to consider the major developmental event of the human cortex to be one of synaptic regression.”

Effects of dopamine D2 receptor antagonism such as catalepsy are more prominent in adolescents than adults.

“In contrast, effects of dopamine D2 receptor antagonism such as catalepsy, or prolonged fixed body posture, are more prominent in adolescents than adults (Spear et al., 1980; Campbell et al., 1988)”

• cites Spear et al., 1980Not checked yet

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• cites Campbell et al., 1988Not checked yet

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Ketamine and phencyclidine do not readily produce hallucinations in children, despite doing so in normal adults.

“Ketamine and phencyclidine do not readily produce hallucinations in children, despite doing so in normal adults (Hirsch et al., 1997)”

• cites Hirsch et al., 1997Not checked yet

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There is an overwhelming increase in brain size, interneuron differentiation, synaptic molecule expression, and GABA and dopamine receptor mRNA levels that indicates gains in synaptic strength predominate in early life and continue during childhood.

“Certainly, there is an overwhelming increase in brain size, in interneuron differentiation, in synaptic molecule expression, and in GABA and dopamine receptor mRNA levels that would indicate that gains in synaptic strength predominate in early life and continue during childhood.”

Many people with schizophrenia show increased susceptibility to behavioral and dopamine-releasing effects of amphetamine.

“Many people with schizophrenia show increased susceptibility to behavioral and dopamine-releasing effects of amphetamine (Lieberman et al., 1987; Laruelle et al., 1996)”

• cites Lieberman et al., 1987Not checked yet

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• cites Laruelle et al., 1996Not checked yet

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Hypersensitivity to typical psychostimulant effects such as locomotor hyperactivity is a benchmark of face validity of animal models of schizophrenia.

“and hypersensitivity to typical psychostimulant effects such as locomotor hyperactivity is a benchmark of face validity of animal models of schizophrenia (Powell and Miyakawa, 2006).”

• cites Powell and Miyakawa, 2006Not checked yet

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The adolescent brain seems to have unique responses to psychoactive drugs compared with children and adults.

“The adolescent brain seems to have unique responses to psychoactive drugs compared with children and adults.”

Numerous reports show that CB1 receptors are altered in schizophrenia.

“and indeed numerous reports show that CB1 receptors are altered in schizophrenia (Zavitsanou et al., 2004; Newell et al., 2006; Eggan et al., 2008, 2010b; Dalton et al., 2011).”

• cites Zavitsanou et al., 2004Not checked yet

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• cites Newell et al., 2006Not checked yet

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• cites Eggan et al., 2008Not checked yet

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The ability of dopamine auto-receptors to suppress subcortical dopamine release matures during adolescence.

“Also, the ability of dopamine auto-receptors to suppress subcortical dopamine release matures during adolescence (Hedner and Lundborg, 1985), which might alter dopamine release following stimulant administration.”

• cites Hedner and Lundborg, 1985Not checked yet

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The schizophrenia prodrome can occur during adolescent years when the human prefrontal cortex is undergoing molecular and functional change.

“The schizophrenia prodrome can occur during the adolescent years when the human prefrontal cortex is undergoing molecular and functional change (Cornblatt et al., 2003).”

• cites Cornblatt et al., 2003Not checked yet

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Increased susceptibility to psychotomimetic effects of THC in people with schizophrenia may be due to aberrant development of the endocannabinoid system during a critical period of change.

“Thus, the increased susceptibility to psychotomimetic effects of THC in people with schizophrenia (D'Souza et al., 2005) may be due to aberrant development of the endocannabinoid system during a critical period of change”

• cites D'Souza et al., 2005Not checked yet

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The major developmental switch at adolescence is the slowing of the exuberant growth period typical of infants, toddlers, and children.

“What appears to be the major developmental switch at adolescence is the slowing of the exuberant growth period typical of infants, toddlers, and children.”

These changes may be more pronounced in rodent pups treated perinatally than in animals exposed to NMDAR antagonists at later developmental stages.

“In addition, these changes may be more pronounced in rodent pups treated perinatally than in animals exposed to NMDAR antagonists at later developmental stages (Mouri et al., 2007).”

• cites Mouri et al., 2007Not checked yet

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Adolescent mammals are less sensitive to locomotor enhancing and cortisol-releasing effects of stimulants such as amphetamine and cocaine compared with adults.

“Adolescent mammals are less sensitive to the locomotor enhancing and cortisol-releasing effects of stimulants such as amphetamine and cocaine compared with adults (Laviola et al., 2002; Zombeck et al., 2010).”

• cites Laviola et al., 2002Not checked yet

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• cites Zombeck et al., 2010Not checked yet

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There is more support for the idea that DRD2 can be elevated in schizophrenia DLPFC.

“There is, however, more support for the idea that DRD2 can be elevated in schizophrenia DLPFC (Hess et al., 1987; Kestler et al., 2001; Tallerico et al., 2001).”

• cites Hess et al., 1987Not checked yet

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• cites Kestler et al., 2001Not checked yet

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• cites Tallerico et al., 2001Not checked yet

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Schizophrenia studies investigating mRNA expression of all five dopamine receptors have found no change in DRD3, DRD4, and DRD5 in the DLPFC.

“Schizophrenia studies investigating mRNA expression of all five dopamine receptors have found no change in DRD3, DRD4, and DRD5 in the DLPFC (Meador-Woodruff et al., 1997; Zhan et al., 2011).”

• cites Meador-Woodruff et al., 1997Not checked yet

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• cites Zhan et al., 2011Not checked yet

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