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Cited by 169Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology Research

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

Open access
Mullins, Caitlin, Fishell, Gord, Tsien, Richard W.·2016·Neuron
DOI 10.1016/j.neuron.2016.02.017PMC PMC5757244
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Abstract

Understanding the mechanisms underlying autism spectrum disorders (ASD) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops, and provide detailed commentary for exemplar genes within each module.

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Crossref · 10.1016/j.neuron.2016.02.017

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Claims the paper makes

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  • Premisecitation

    Systematic study has found hundreds of direct protein-protein interactions among products of ASD-implicated genes, including a network involving SHANK and TSC1.

    “For example, systematic study has uncovered hundreds of direct protein-protein interactions amongst products of genes previously implicated in ASD, including a network involving SHANK and TSC1 (Sakai et al., 2011).”
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    Exome sequencing has found de novo single nucleotide variations and indels that segregate with ASD.

    “Exome sequencing has uncovered de novo single nucleotide variations (SNVs) and insertion/deletion (indel) mutations that segregate with ASD.”
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    Voineagu et al. found two modules highly correlated with ASD status in postmortem brain samples.

    “Voineagu et al. performed comparative transcriptomic analysis of post-mortem ASD brain samples and found two modules highly correlated with ASD status (Voineagu et al., 2011).”
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    ASD is strongly heritable, as indicated by higher risk among people with an affected twin or sibling.

    “ASD is highly heritable, as judged by heightened risk for individuals with an affected twin or sibling (Bailey et al., 1995; Folstein and Rutter, 1977a, b).”
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    Transcriptomic studies of postmortem tissue have found clusters of genes, called modules, whose transcripts co-vary.

    “In a complementary approach, transcriptomic studies in postmortem tissue have uncovered clusters of genes (so-called modules) whose transcripts co-vary.”
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    • cites Zhang and Horvath, 2005 source

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    Premisecitation

    Genetic studies have identified about 20-30% of the sought-after ASD genes.

    “Thus, it seems remarkable that within just the last few years, genetic studies have identified a sizeable fraction of the sought-after ASD genes, roughly 20-30% according to most estimates (Bourgeron, 2015; Krumm et al., 2014; Schaaf and Zoghbi, 2011).”
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    Premisecitation

    Heritability estimates for ASD fall between 52% and 90%, with one notable exception.

    “With one notable exception (Hallmayer et al., 2011), heritability estimates range from 52-90% (Chen et al., 2015; De Rubeis and Buxbaum, 2015a, b; Gaugler et al., 2014; Rosenberg et al., 2009; Sandin et al., 2014; Toro et al., 2010).”
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    Premisecitation

    The framework starts from a hypothetical scheme for autoregulation of neuronal firing proposed by Abbott, Golowasch, Marder, and Turrigiano.

    “The starting point is a hypothetical scheme for the autoregulation of neuronal firing, proposed by Abbott, Golowasch, Marder, and Turrigiano at Brandeis in a prescient series of papers two decades ago (LeMasson et al., 1993; Marder et al., 1996; Siegel et al., 1994) (Fig. 1).”
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    The genetics of ASD is very complex, with current estimates involving roughly 400 to 1200 genes.

    “The genetic landscape of ASD is extremely complex, involving some 400-1200 genes according to current best estimates (De Rubeis and Buxbaum, 2015a; Geschwind and State, 2015; Ronemus et al., 2014; Willsey and State, 2015).”
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    One of these modules, M12, was downregulated in ASD cases and contained genes involved in synaptic function, vesicular transport, and neuronal projection.

    “One of these modules (M12) was downregulated in ASD cases, contained genes known for involvement in synaptic function, vesicular transport, and neuronal projection, and was inferred to be causally involved in ASD pathophysiology.”
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    Genetic factors make a substantial contribution to ASD and probably interact with environmental factors to shape clinical outcome.

    “Thus, genetic factors contribute substantially, and likely combine with environmental effects to guide clinical outcome (Bourgeron, 2015).”
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    GWAS for ASD have not yet achieved desired reproducibility, most likely because they have been underpowered.

    “Genome Wide Association Studies (GWAS) have not yet reached desired reproducibility, most likely because they have been underpowered (typically 2,000-5,000 patients, far fewer than the ∼50,000 that drove a highly successful GWAS in schizophrenia (Cross-Disorder Group of the Psychiatric Genomics et al., 2013)).”
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    Premisecitation

    CTNNB1 mutations appear among suggestive de novo ASD risk mutations, and about 40% of 126 mutations map to a β-catenin/chromatin remodeling network.

    “Mutation of the gene encoding β-catenin, CTNNB1, has been found among suggestive de novo ASD risk contributing mutations (de Ligt et al., 2012; O'Roak et al., 2012b); furthermore, ∼40% of those 126 mutations map to a highly interconnected β-catenin/chromatin remodeling network (O'Roak et al., 2012b).”
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    Premisereasoning

    Genetic studies also implicate sodium and potassium channels in ASD, but their roles are activity-related in a different way.

    “Although genetic studies also implicate sodium and potassium channels, their roles in ASD are activity-related in a somewhat different way.”
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    Interpretationreasoning

    The scheme permits genes to be assigned putatively into functional rather than anatomical groupings.

    “It allows the putative assignment of genes into functional rather than anatomical groupings, as we have attempted in Table 1.”
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    Free cytosolic β-catenin is phosphorylated by GSK3β and marked for proteosomal degradation.

    “On the other hand, free cytosolic β-catenin is phosphorylated by GSK3β (part of a destruction complex), and thus marked for proteosomal degradation.”
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    Interpretationreasoning

    The neurologically penetrant mutation produces an abnormal voltage setpoint, consistent with a disturbed regulatory feedback loop.

    “Thus, the neurologically penetrant mutation gives an abnormal voltage setpoint, in keeping with the premise of a disturbed regulatory feedback loop.”
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    β-catenin also takes part in cell-cell interactions through cadherin, independently of Wnt signaling.

    “However, it is worth noting that β-catenin also participates in cell-cell interactions via cadherin (CDH8 being a candidate ASD gene, see Table 1), independent of Wnt signaling.”
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    Interpretationreasoning

    The effector mechanism uses a feedback connection to oppose deviation of the sensed variable from its set point.

    “The effector mechanism works through a feedback connection to counteract variation of the sensed variable from its designated set point.”
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    • The authors state this as an assumption: Neuronal firing can be modeled as the controlled variable in a negative feedback loop for autoregulation.

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    Interpretationcitation

    Changes in a neuron's firing rate alter Ca2+ channel activity, which acts as a sensor driving an effector mechanism.

    “Changes in a neuron's firing rate result in alterations in Ca2+ channel activity, which serves as a sensor that drives an effector mechanism.”
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    • The authors state this as an assumption: Neuronal firing can be modeled as the controlled variable in a negative feedback loop for autoregulation.

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    Interpretationreasoning

    The chemical ligand for such sensors can be a neurotransmitter like glutamate, a neurotrophin like BDNF, or a glycoprotein such as Wnt.

    “The chemical ligand can be a neurotransmitter like glutamate, a neurotrophin like BDNF, or a glycoprotein such as Wnt.”
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    Interpretationcitation

    A prototypical homeostat protein is a Ca2+ channel that links membrane potential changes to downstream biochemical events.

    “A prototypical homeostat protein would be a Ca2+ channel that couples membrane potential changes to downstream biochemical events (see Diverse systems for sensor-mediated control of gene expression).”
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    • The authors state this as an assumption: Neuronal firing can be modeled as the controlled variable in a negative feedback loop for autoregulation.

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    Premisenone given

    Canonical Wnt signaling indirectly stabilizes β-catenin, enabling its movement to the nucleus and linking extracellular signals to nuclear gene expression.

    “Canonical Wnt signaling acts, indirectly, to enhance the stability of β-catenin, allowing its translocation from the cell surface to the nucleus, thereby connecting extracellular signals to the regulation of nuclear gene expression by downstream transcriptional machinery (Fig. 3).”
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    Interpretationreasoning

    Ca2+ channels can send an intracellular signal, whereas Na+ channels only drive electrical firing; neither Na+ nor K+ ions are established biochemical messengers, and their ultimate impact is likely mediated by Ca2+ channels.

    “While Ca2+ channels can send an intracellular signal, Na+ channels merely drive electrical firing, and neither Na+ nor K+ ions are established biochemical messengers; their ultimate impact is likely mediated by Ca2+ channels.”
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    Premisecitation

    Wnt signaling can proceed through the canonical Wnt/β-catenin pathway or through multiple non-canonical pathways, some of which involve Ca2+ signaling.

    “Signaling downstream of the proteolipid ligands known as Wnts can proceed via the canonical Wnt/β-catenin pathway (Nelson and Nusse, 2004), or through multiple non-canonical pathways, not mediated by β-catenin (Gordon and Nusse, 2006; Rosso et al., 2005; Salinas and Zou, 2008), with some involving Ca2+ signaling (Kohn and Moon, 2005).”
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    Interpretationreasoning

    The concept of homeostat proteins can be broadened to sensors that respond to chemical signals and support downstream biochemical signaling.

    “With this distinction in mind, we generalize the concept of homeostat proteins to sensors that respond to chemical signals and support downstream biochemical signaling.”
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    Premisecitation

    Neuronal depolarization communication proceeds through various signaling cascades and regulates intranuclear events such as enhancer recruitment, transcription factor activation, and alternative pre-mRNA splicing.

    “Communication of neuronal depolarization proceeds by a variety of signaling cascades and regulates intranuclear events such as enhancer recruitment (Kim et al., 2010), transcription factor activation (Ebert and Greenberg, 2013) and alternative pre-mRNA splicing (Li et al., 2007).”
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    Interpretationreasoning

    In neuronal homeostasis, the feedback connection opposes change and is therefore negative feedback.

    “In neuronal homeostasis, as in HVAC systems, the feedback connection operates to oppose change, hence its designation as negative feedback.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Neuronal firing can be modeled as the controlled variable in a negative feedback loop for autoregulation.

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    Interpretationreasoning

    A homeostatic sensor detects perturbations or dysfunction elsewhere in the system and can itself fail.

    “Like the metaphorical room thermostat, it detects perturbations or dysfunction in other parts of the system, and can itself be prone to failure.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Neuronal firing can be modeled as the controlled variable in a negative feedback loop for autoregulation.

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    Premisenone given

    Point mutations that cause ASD generally sensitize voltage-dependent gating of Ca2+ channels, shifting activation to more negative potentials by about 10 mV.

    “The point mutations that give rise to ASD generally sensitize voltage-dependent gating of Ca2+ channels, shifting its activation to more negative potentials by ∼10 mV (e.g. G406R in CACNA1C, but not G402S).”
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    Premisecitation

    Only 3% of the transcriptome is expressed in an activity-dependent manner, but a much larger fraction of ASD-implicated genes show activity-dependent expression.

    “The idea that defects in activity-induced gene expression contribute to ASD was initially based on a provocative realization: while only 3% of the transcriptome is expressed in an activity-dependent manner, a far greater percentage of ASD implicated genes display activity-dependent expression (Kelleher and Bear, 2008; Morrow et al., 2008).”
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    Pore-forming and auxiliary subunits of several Ca2+ channels are encoded by known autism-associated genes.

    “Indeed, pore-forming and auxiliary subunits of several Ca2+ channels are encoded by known autism-associated genes.”
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    Interpretationreasoning

    The homeostatic sensor can detect changes in the controlled variable and trigger effector mechanisms, including altered nuclear or dendritic events.

    “Once again, the homeostatic sensor can detect variations in the controlled variable and trigger one or more effector mechanisms, including altered nuclear or dendritic events.”
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    Study design and conductreasoning

    Many entries in Table 1 do not reach genome-wide significance but are included because they fit a pathophysiological scenario.

    “Many of the entries do not reach genome-wide significance based on current data but are included because of their fit with a pathophysiological scenario, and are annotated with a footnote.”
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    Interpretationreasoning

    Feedback mechanisms extend beyond electrical activity to autoregulation of neuronal biochemistry, cell biology, and microcircuit performance.

    “It exemplifies a variety of feedback mechanisms — not just those involved in regulating electrical activity as illustrated here, but also extending to autoregulation of neuronal biochemistry, cell biology, and microcircuit performance.”
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    • The authors state this as an assumption: Neuronal firing can be modeled as the controlled variable in a negative feedback loop for autoregulation.

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    Premisecitation

    Wnt signaling has multiple roles, including in cell adhesion, dendritic remodeling, and early brain development.

    “However, as clearly summarized by Kalkman (Kalkman, 2012), one must recognize the multiple roles of Wnt signaling, not only in cell adhesion and dendritic remodeling but also in early brain development (Rosso et al., 2005; Salinas and Zou, 2008; Ueda et al., 2008; Wayman et al., 2006; Yu and Malenka, 2003).”
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    Interpretationreasoning

    In the homeostatic framework, a mutation in any single element can affect the whole loop and can also impact different routes through the overall loop.

    “In the homeostatic framework in Figure 2, a mutation in any individual element can have effects throughout the loop, and can also impact different routes through the overall loop.”
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    Premisecitation

    CaMKIV phosphorylation regulates RBFOX1 activity, and RBFOX1 controls alternative splicing and stability of many mRNAs involved in synaptic and neuronal signaling, including CAMK2G, GRIN1, CNTNAP2, NRCAM, and RBFOX1 itself.

    “For example, CaMKIV phosphorylation regulates the activity of RBFOX1, a factor that controls the alternative-splicing and stability of many mRNAs involved in synaptic and neuronal signaling, including CAMK2G, GRIN1, CNTNAP2, NRCAM and RBFOX1 itself (Gehman et al., 2011).”
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    Premisecitation

    The Ca2+ rise relevant for nuclear signaling must occur within 1-2 μm of the channel mouth, but is connected to the nucleus by a signaling pathway.

    “The Ca2+ rise that matters for signaling to the nucleus must occur within 1-2 μm of the channel mouth (Deisseroth et al., 1996), but is linked to the nucleus by a signaling pathway (Ma et al., 2014), depicted in Fig. 4.”
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    Premisecitation

    FXS is a relatively common inherited intellectual disability often associated with ASD symptoms including perseverative behaviors, speech and sensory difficulties, and disrupted sleep.

    “This relatively common form of inherited intellectual disability is often associated with symptoms of ASD, including perseverative behaviors, speech and sensory difficulties, and disrupted sleep (Kidd et al., 2014).”
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    Premisecitation

    In hippocampal slices from Tsc2+/- mice, LTP is enhanced, and protocols that normally induce decaying E-LTP produce long-lasting L-LTP.

    “In hippocampal slices from Tsc2+/- mice, LTP is enhanced (Fig. 5A1); as a result, protocols that normally induce a decaying form of potentiation (E-LTP) result in the generation of long-lasting LTP (L-LTP) (Ehninger et al., 2008).”
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    Premisecitation

    TSC arises from heterozygous mutations in TSC1 or TSC2 and is frequently associated with long-term and working memory deficits, intellectual disability, ASD, and epilepsy.

    “Frequently associated with deficits in long-term and working memory, along with intellectual disability, ASD, and epilepsy, TSC arises from heterozygous mutations in the TSC1 or TSC2 genes (Ehninger et al., 2009; Ehninger et al., 2008; Kong et al., 2014; Tsai et al., 2012).”
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    Interpretationreasoning

    Nearby spines experience a decline in local glutamate such that mGluRs, but not NMDARs, are strongly activated, leaving mGluR signaling to predominate in a penumbra near the spine destined for LTP.

    “Thus, nearby spines must experience a decline in local [Glu] such that the more sensitive mGluRs, but not NMDARs, are strongly activated, leaving mGluR signaling to predominate in a penumbra of spines near the one destined to be strengthened via LTP.”
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    Premisecitation

    After saturating LTP, single spines enlarge and postsynaptic area increases.

    “After LTP, single spines enlarged and the postsynaptic area increased, as expected.”
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    Premisecitation

    Genetic alterations in FMR1 cause Fragile X Syndrome.

    “Genetic alterations in the Fragile X mental retardation 1 gene (FMR1) give rise to Fragile X Syndrome (FXS) (Verkerk et al., 1991).”
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    Premisecitation

    Converging evidence suggests that fetal testosterone may contribute to the higher prevalence of ASD in males than females (about 4:1).

    “Knowledge of environmental factors is growing, as exemplified by converging evidence that fetal testosterone may contribute to the preponderance of ASD in males vs. females (∼4:1) (Baron-Cohen et al., 2011).”
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    Premisecitation

    Mutations in CREBBP cause Rubenstein-Taybi syndrome, a disorder with prominent autistic features.

    “Mutations in CREBBP give rise to Rubenstein-Taybi syndrome, a disorder with prominent autistic features (Petrij et al., 1995).”
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    Premisecitation

    Rabinowitch and Segev theorized that strengthening of single spines by Hebbian plasticity is chained to compensatory weakening of nearby spines.

    “For example, Rabinowitch & Segev theorized about dendritic mechanisms of local regulation, where the strengthening of single spines by Hebbian plasticity is chained to compensatory mechanisms for weakening other spines nearby (Fig. 6A) (Rabinowitch and Segev, 2008).”
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    Premisecitation

    LTD is attenuated in Tsc2+/- mice and in the Tsc2ΔRG loss-of-function mutant.

    “Furthermore, LTD is attenuated, both in Tsc2+/- (Auerbach et al., 2011; Bateup et al., 2011), and in a loss of function mutant, Tsc2ΔRG, that weakens translational braking (Chevere-Torres et al., 2012).”
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    Premisecitation

    S6K1 acts downstream of TORC1 to drive EIF4E-regulated initiation of translation and dampens translation of FMRP-regulated mRNAs by phosphorylating FMRP.

    “S6K1 has been shown to act downstream of TORC1 to drive EIF4E-regulated initiation of translation (Richter et al., 2015), and dampens translation of FMRP-regulated mRNAs by phosphorylating FMRP (Santoro et al., 2012).”
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    Premisenone given

    Adjustments of inhibitory neuron firing or inhibitory transmission can operate much more rapidly than feedback by transcriptional or translational loops.

    “Regardless of the specific circuit, adjustments of inhibitory neuron firing or inhibitory transmission can operate much more rapidly than feedback by transcriptional or translational loops.”
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    Premisecitation

    SCN1A loss-of-function impairs sodium currents and spiking in hippocampal GABAergic interneurons without a detectable effect on excitatory pyramidal neurons.

    “SCN1A loss-of-function impairs sodium currents and spiking in hippocampal GABAergic interneurons, without a detectable effect on excitatory pyramidal neurons.”
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    Interpretationreasoning

    E:I coordination can be viewed as analogous to transcription and translation autoregulation, with control of inhibition filling a critical kinetic gap.

    “As a consequence, E:I coordination can be viewed as made of the same cloth as transcription and translation autoregulation — with the control of inhibition filling in a critical kinetic gap.”
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    Premisecitation

    Boys who inherit ARX mutations primarily manifest epilepsy, mental retardation or movement disorders, and some also have ASD.

    “Boys that inherit mutations in ARX primarily manifest epilepsy, mental retardation or movement disorders, and some also have ASD (Turner et al., 2002).”
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    Interpretationreasoning

    SHANK3 is one of the genes with the strongest statistical links to ASD, but because its protein functions postsynaptically in both excitatory and inhibitory populations, its effects on E:I coordination are not simple to pin down.

    “SHANK3 is one of the genes with the strongest statistical links to ASD, but as the protein functions postsynaptically in both excitatory and inhibitory populations, its effects on E:I coordination, while very important, are not simple to pin down.”
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    Premisecitation

    Loss of ARX severely impairs interneuron development because Arx is a repressor that orchestrates interneuron differentiation.

    “Loss of ARX severely impairs interneuron development (Vogt et al., 2014), as Arx is a repressor that functions to orchestrate interneuron differentiation.”
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    Premisecitation

    Of 84 genes abnormally regulated in Arx-/- mice, many are involved in neuronal development and some have been implicated in ASD, epilepsy, and mental retardation.

    “Of the 84 genes found to be abnormally regulated in Arx-/- mice (Fulp et al., 2008), many are involved in neuronal development (cell migration, axonal guidance, neurogenesis) and some have been in implicated in ASD, epilepsy, and mental retardation, befitting clinical features seen in patients with ARX mutations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fulp et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    About 30% of patients with ASD also have epilepsy, and about 30% of patients with epilepsy have been diagnosed with ASD.

    “As they argued, and as recent studies have reminded us, 30% of patients with an ASD also have epilepsy, and 30% of patients with epilepsy have been diagnosed with an ASD (Bolton et al., 2011; Brooks-Kayal, 2010; Tuchman et al., 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bolton et al., 2011 source

      Not checked in the free run.

    • cites Brooks-Kayal, 2010 source

      Not checked in the free run.

    • cites Tuchman et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When Ca2+ is high, activated βCaMKII can participate in SAPAP trafficking and increase AMPAR incorporation, enabling spine remodeling and synaptic strengthening.

    “In contrast, when Ca2+ is high, activated βCaMKII can participate in SAPAP trafficking and increase incorporation of AMPARs, enabling spine remodeling and synaptic strengthening (Shin et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shin et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ARX is an X-linked gene (Xp22.1) that encodes the first transcription factor implicated in causing autism.

    “(Aristaless related homeobox gene), an X-linked gene (Xp22.1), encodes the first transcription factor (TF) implicated in causing autism (Rubenstein and Merzenich, 2003; Turner et al., 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rubenstein and Merzenich, 2003 source

      Not checked in the free run.

    • cites Turner et al., 2002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    More than 300 mutations in SCN1A exons account for about 70% of Dravet syndrome cases; most are truncations or deletions disrupting voltage sensing or ion conduction, and the remaining 30% likely act through effects on SCN1A expression.

    “Identification of >300 mutations in SCN1A exons accounts for ∼70% of DS cases; and most mutations are truncations or deletions that disrupt voltage sensing or ion conduction, with the remaining 30% likely acting through their impact on SCN1A expression (Oakley et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Oakley et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This de-repression increases abundance of regulatory proteins such as Arc, CaMKIIα, PSD95, and CaMKIIβ, setting up the spine for a binary decision between LTD and LTP.

    “This in turn will increase the abundance of regulatory proteins such as Arc, CaMKIIα, PSD95, and CaMKIIβ (Darnell et al., 2011; Muddashetty et al., 2011; Niere et al., 2012; Park et al., 2008; Stefanovic et al., 2015), setting up the spine for a binary decision, to undergo LTD or LTP.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Darnell et al., 2011 source

      Not checked in the free run.

    • cites Muddashetty et al., 2011 source

      Not checked in the free run.

    • cites Niere et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    βCaMKII serves as an activity sensor: when Ca2+ is low, CaM-free, kinase-deactivated βCaMKII interacts with Arc and facilitates Arc-mediated endocytosis of AMPARs.

    “Okuno et al. have shown that βCaMKII serves as an activity sensor; when Ca2+ is low, CaM-free, kinase-deactivated βCaMKII interacts directly with Arc and helps facilitate Arc-mediated endocytosis of AMPARs (Okuno et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Okuno et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    During normal synaptic communication, inhibitory current is typically several-fold larger than excitatory current at the neuron's resting potential.

    “During normal synaptic communication, the inhibitory current is typically several-fold larger than the excitatory current at the neuron's resting potential.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The decision between strengthening and weakening likely uses local protein synthesis as a platform but is ultimately governed by βCaMKII as a local sensor of activity-dependent Ca2+ rises.

    “Thus, the decision between strengthening and weakening likely employs local protein synthesis as a platform, but is ultimately governed by βCaMKII as a local sensor of activity-dependent rises in Ca2+.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The ASD-associated SHANK family are scaffolding proteins in the postsynaptic density that connect membrane proteins with the actin cytoskeleton of the dendritic spine and are crucial for synapse formation and maintenance.

    “For example, the ASD-associated SHANK family are scaffolding proteins present in the postsynaptic density that serve a crucial role in synapse formation and maintenance by connecting proteins at the membrane with the actin cytoskeleton of the dendritic spine (Guilmatre et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Guilmatre et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreased inhibitory firing leads to dysregulation of inhibition, the likely cause of seizures in Dravet syndrome patients.

    “In turn, decreased inhibitory firing leads to dysregulation of inhibition, the likely cause of seizures in DS patients (Oakley et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Oakley et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PP2A removes the FMRP brake and interferes with NMDA signaling by dephosphorylating and deactivating ERK1/2.

    “Furthermore, PP2A not only removes the FMRP brake (Niere et al., 2012) but also interferes with NMDA signaling by dephosphorylating and deactivating ERK1/2 (Alessi et al., 1995).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Niere et al., 2012 source

      Not checked in the free run.

    • cites Alessi et al., 1995 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dysfunction of either FMRP or TSC1/2 regulation would disrupt overall LTP:LTD coordination and potentially circuit-wide E:I coordination, and thus be deleterious for behavioral plasticity.

    “Accordingly, dysfunction of either mode of regulation would be disruptive for overall LTP:LTD coordination (and potentially circuit-wide E:I coordination), and thus deleterious for behavioral plasticity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    50-70% of EEG or MEG sleep recordings from children with autism show sharp spike activity indicative of unstable cortical networks.

    “R&M went on to note that 50-70% of EEG or MEG sleep recordings from children with autism show evidence of sharp spike activity, indicative of unstable cortical networks.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rubenstein and Merzenich, 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Timothy Syndrome-causing point mutations in CACNA1C disrupt development of neuronal dendrites, bone, and skin, and also affect ongoing electrical function in heart and brain.

    “For example, point mutations in CACNA1C that underlie Timothy Syndrome perturb the development of neuronal dendrites (Krey and Dolmetsch, 2007), bones (Ramachandran et al., 2013), and skin (Yucel et al., 2013), as well as ongoing electrophysiological function of heart and brain (Krey and Dolmetsch, 2007; Splawski et al., 2005; Splawski et al., 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Krey and Dolmetsch, 2007 source

      Not checked in the free run.

    • cites Ramachandran et al., 2013 source

      Not checked in the free run.

    • cites Yucel et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At about 11 weeks post-conception, an early transition is marked by reduced expression of a module that inhibits neuronal differentiation and increased expression of one that promotes it.

    “An early transition (∼11 weeks post-conception) is indicated by attenuation of a gene module that opposes neuronal differentiation, giving way to one that favors it.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Parikshak et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Some neurodevelopmental stages might operate without feedback control, instead following a one-way sequence such as a transcription factor cascade.

    “Alternatively, certain stages of neurodevelopment may not be driven by feedback regulation, but may harness a unidirectional chain of events like a transcription factor cascade, tuned by feedback on an evolutionary scale but not by immediate servo control.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: During early neurodevelopment, signaling between cells, rather than cell-autonomous activity-dependent homeostasis, is the primary mode.

  • May combine two claims.

    Premisecitation

    In 37 Dravet syndrome patients, about 25% met criteria for autism and about 95% had intellectual disability, with more severe deficits in those with autism.

    “Closer examination of autistic features in 37 DS patients showed that ∼25% met the criteria for autism, and ∼95% presented with intellectual disability, with more severe deficits in those with autism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Li et al., 2011

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    E:I dyscoordination can influence other neuronal functions, including plasticity and activity-dependent gene expression.

    “Further, E:I dyscoordination is capable of influencing a variety of other neuronal functions, including plasticity and activity-dependent gene expression.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The expanded feedback arrangement offers multiple choices for sensor, effector mechanisms, feedback connections, and controlled variables, greatly expanding possible ways a neuron or circuit could use feedback to keep physiological variables close to setpoints.

    “However, the expanded feedback arrangement in Fig. 2 offers multiple choices for sensor, effector mechanisms, feedback connections and controlled variables, among further possibilities not enumerated. In combination, such options greatly expand the possible ways that a neuron or circuit could use feedback to keep physiological variables close to their setpoints.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Autoregulation may be confined to a single cell in some instances, while in others it is distributed across a whole circuit and its chemical signaling state.

    “In some cases, the autoregulation is cell-autonomous, in others it is a distributed property of an entire circuit and its state of chemical signaling.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Similar principles govern the asymmetric division of neuroblasts and ganglion mother cells, the precursors of glia and neurons.

    “Analogous principles apply to the asymmetric cell division between neuroblasts and ganglion mother cells that give rise to glia and neurons (Anderson and Jan, 1997; Knoblich, 1997).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Anderson and Jan, 1997

      Not checked in the free run.

    • cites Knoblich, 1997 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Mutations disrupting early transcriptional cascades in development probably cause lethality, so they are less likely to appear as direct causes of neuropsychiatric disorders.

    “Genetic insults that disrupt early developmental transcriptional cascades likely result in lethality and are therefore underrepresented as proximal causes of neuropsychiatric diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Computational analyses indicate that these processes are linked through FMRP-mediated translational control and shared transcription factors.

    “Bioinformatics analyses suggest that these processes are connected via translational regulation by FMRP and transcriptional co-regulation by common transcription factors, mechanisms touched upon elsewhere in this review.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Parikshak et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Wnt signaling is known to influence early cell-cell interactions and to direct axon and dendrite migration and differentiation.

    “Likewise, Wnt signaling is known to shape early cell-cell interactions (Nelson and Nusse, 2004), and to guide cell migration and differentiation of axons and dendrites (Salinas and Zou, 2008; Yu and Malenka, 2003);”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Nelson and Nusse, 2004

      Not checked in the free run.

    • cites Salinas and Zou, 2008 source

      Not checked in the free run.

    • cites Yu and Malenka, 2003

      Not checked in the free run.

76 of 76

  • The authors state this as an assumption.

    Neuronal firing can be modeled as the controlled variable in a negative feedback loop for autoregulation.

    “We have adapted this computational model to diagram neuronal firing as the controlled variable whose variations are delimited by a feedback system.”

  • The paper relies on this without support.

    Findings from syndromic forms of ASD and from animal models can be generalized to idiopathic human ASD.

    “Here we compare two modes of local translational regulation, each involving well-known ASD-related signaling proteins, FMRP and TSC1/2.”

  • The paper relies on this without support.

    The signaling mechanisms and feedback loops described are conserved between rodents and humans.

    “In hippocampal slices from Tsc2+/- mice, LTP is enhanced (Fig. 5A1); as a result, protocols that normally induce a decaying form of potentiation (E-LTP) result in the generation of long-lasting LTP (L-LTP) (Ehninger et al., 2008).”

  • The paper relies on this without support.

    ASD can be treated as a single spectrum for the purpose of constructing a unifying pathophysiological scheme.

    “Here we side with those who prefer to keep focused on the entire spectrum (like Hans Asperger and the committee that made DSM-V) rather than split it into sub-disorders (like Leo Kanner and the creators of DSM-IV).”

  • The paper relies on this without support.

    During early neurodevelopment, signaling between cells, rather than cell-autonomous activity-dependent homeostasis, is the primary mode.

    “Early neurodevelopment relies on cell-to-cell chemical signaling rather cell-autonomous, activity-dependent homeostasis like that in Fig. 1.”
5 of 5

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?

  • The functions of the proteins encoded by these risk genes are substantially diverse, preventing a clear a priori prediction of the affected brain cell types, developmental processes, and molecular pathways during neurodevelopment.

    “there is substantial diversity in the function of the gene products that these genes encode, precluding a clear a priori prediction of the underlying brain cell types, developmental processes, and molecular pathways affected during neurodevelopment (7).”

    From In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes (2020) · cites this paper as [7]

  • The overlap supports a model of ASD pathophysiology based on changes in excitation/inhibition balance and neuronal activity and suggests that alterations in transcript structure are likely important.

    “This overlap supports a model of ASD pathophysiology based on changes in the balance of excitation and inhibition and in neuronal activity22 and suggests that alterations in transcript structure are likely to be an important component.”

    From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [22]

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Related

Authors
Mullins, C., Fishell, G., & Tsien, R. W.
Affiliations
NYU Langone Health (US)
Corresponding author
Tsien, Richard W.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2016-03
Volume
89
Issue
6
Pages
1131-1156
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2016.02.017
PMC
PMC5757244
OpenAlex
W2301446452
Semantic Scholar
4697e7cdb231088d6a4dfe267102e29f4f6f204e
Cited by
167
References
261
Citations by year
2026: 3 · 2025: 12 · 2024: 10 · 2023: 11 · 2022: 13 · 2021: 17 · 2020: 22 · 2019: 15 · 2018: 21 · 2017: 23 · 2016: 20
FWCI
2.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (MH071739, T32MH096331, R01MH071739, R37MH071739)
  • National Institute on Drug Abuse (DA040484, R01DA040484)
  • National Institute of General Medical Sciences (GM058234, R01GM058234)
  • National Institute of Neurological Disorders and Stroke (NS 24067, R01NS024067, R01NS081297)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
autism spectrum disorder, autoregulatory loop, homeostatic regulation, synaptic homeostasis, neuronal electrical activity, negative feedback
MeSH terms
Autism Spectrum Disorder, Brain, Gene Expression Regulation, Humans, Models, Biological, Nerve Net, Neurons, Signal Transduction, Feedback, Physiological

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

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