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Cited by 145Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models

Open access
O'Donnell, P.·2011·Schizophrenia Bulletin
DOI 10.1093/schbul/sbr028PMC PMC3080677
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Abstract

Schizophrenia and related mental disorders are common and devastating conditions for which we have a limited understanding of their origin and mechanisms. Although this apparent lack of progress despite vast research efforts could be due to difficulties in reproducing the disease in animals, animal work is now providing important insight onto possible pathophysiological changes in the brain. Postmortem studies of human brains have provided data indicating altered local inhibitory circuits in the cerebral cortex in schizophrenia and different developmental, pharmacological, and genetic animal models converge in revealing deficits in cortical interneuron function that can be associated with neurophysiological and behavioral alterations resembling aspects of the disease. Schizophrenia pathophysiology has a complex developmental trajectory because overt symptoms become evident during late adolescence despite earlier events contributing to the disease. The late incidence of schizophrenia can be explained by the protracted maturation of brain circuits implicated in the disease, particularly during adolescence. Excitatory and inhibitory processes in cortical circuits are tightly modulated by dopamine (DA), and many aspects of DA function in cortical regions acquire their adult profile during adolescence. This maturation fails to occur or is abnormal in several different rodent models of schizophrenia, yielding a number of functional and behavioral deficits relevant to the disease. Thus, periadolescent changes in cortical inhibitory circuits are a critical developmental stage likely implicated in the transition to schizophrenia. These observations provide the foundation for novel research-based therapeutic approaches and perhaps will even lead to ways to prevent the progression of the disease in predisposed subjects.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that schizophrenia may arise from a failure in periadolescent maturation of cortical inhibitory circuits, especially dopamine modulation of prefrontal GABA interneurons, leading to cortical disinhibition. Converging rodent developmental, pharmacological, and genetic models show parvalbumin interneuron deficits that emerge during late adolescence, suggesting targets for treatment or prevention.

Key findings

  • Postmortem human studies indicate altered local inhibitory circuits in the cerebral cortex in schizophrenia, and animal models converge on cortical interneuron dysfunction associated with neurophysiological and behavioral alterations resembling aspects of the disease.
  • In rodent prefrontal cortex, dopamine modulation of interneurons matures during adolescence: in juvenile rats D1 agonists increase GABA interneuron firing while D2 agonists have weak or no effect, whereas in adult PFC D2 agonists become strongly excitatory over fast-spiking interneurons, allowing more efficient attenuation of cortico-cortical synaptic responses.
  • The neonatal ventral hippocampal lesion (NVHL) model has nearly 100 published articles and more than 20 laboratories using it; adult rats show hyperlocomotion, increased response to novelty, abnormal social behaviors, exaggerated responses to stress, stimulants and NMDA antagonists, working memory deficits, perseveration, sensorimotor gating deficits, and deficient activation of fast-spiking GABA interneurons by D2 agonists, with most alterations emerging during adolescence.
  • Other developmental and genetic models also show interneuron-related deficits: prenatal MAM yields fewer parvalbumin-expressing interneurons and loss of high-frequency oscillations; early postnatal PCP reduces adult PV+ neurons in PFC; isolation rearing reduces hippocampal PV+ cells; ErbB4 knock-out mice show reduced PV interneurons and loss of kainate-induced gamma oscillation power; dominant-negative DISC1 mice show reduced PV in medial PFC; and NR1 knockout selectively in PV+ cortical interneurons yields sensorimotor gating deficits, working memory deficits, hyperlocomotion, and enhanced response to stimulants.

Methods

  • Narrative review, not a primary experimental study; it synthesizes postmortem human findings and rodent models of schizophrenia.
  • Models discussed include pharmacological NMDA antagonist models, developmental manipulations such as prenatal MAM and neonatal ventral hippocampal lesion, perinatal immune challenge, social isolation, and genetic manipulations including ErbB4, DISC1, and interneuron-selective NR1 knockout.
  • Main analysis is qualitative convergence across models, with no systematic search, meta-analysis, or new data reported.

Limitations

  • The paper states that construct validity is limited in schizophrenia because the origin or mechanisms of the disease are unknown and therefore cannot be reproduced in an animal model; it also notes that animal models cannot reproduce all symptoms, and that the NVHL model includes a small lesion not observed in schizophrenia patients and is not likely to model hippocampal pathology in schizophrenia.
  • The paper notes conflicting reports about NMDA receptor currents in PFC interneurons and suggests slice preparations may lose a critical input that drives cortical interneurons, so they may not reflect the in vivo condition; genetic models are described as still in early stages.
  • Evident from the text: this is a narrative review without a systematic search strategy or quantitative synthesis, and its conclusions rely on convergence across cited studies rather than primary data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/schbul/sbr028

Cites

82 of 82 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    The late incidence of schizophrenia can be explained by the protracted maturation of brain circuits implicated in the disease, particularly during adolescence.

    “The late incidence of schizophrenia can be explained by the protracted maturation of brain circuits implicated in the disease, particularly during adolescence.”
    Quote in the paperSubstantial claim
  • Premisecitation

    DA receptors reach stable adult levels by the end of the adolescent period.

    “DA receptors reach stable adult levels by the end of the adolescent period, 5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] source

      Not checked in the free run.

  • Premisecitation

    The prefrontal cortex (PFC) and hippocampus stand out as major regions affected in schizophrenia.

    “The prefrontal cortex (PFC) and hippocampus stand out as major regions affected in schizophrenia”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] source

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    • cites [3] source

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  • Premisenone given

    Many aspects of DA function in cortical regions acquire their adult profile during adolescence.

    “many aspects of DA function in cortical regions acquire their adult profile during adolescence.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Symptoms of schizophrenia do not manifest fully until late adolescence.

    “symptoms do not manifest fully until late adolescence.1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] source

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  • May combine two claims. 16
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingcitation

    In NVHL rats, there is loss of transient increase in beta oscillations and excessive pyramidal cell firing during the decision instance of a choice task.

    “In NVHL rats, we have recently shown loss of transient increase in beta oscillations and excessive pyramidal cell firing during the decision instance of a choice task.72”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] source

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    Findingcitation

    In that study, NVHL rats showed deficits in reversal learning, a process that correlated with the increase in beta power in controls.

    “In that study, NVHL rats showed deficits in reversal learning, a process that correlated with the increase in beta power in controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] source

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

    Premisenone given

    Excitatory and inhibitory processes in cortical circuits are tightly modulated by dopamine (DA).

    “Excitatory and inhibitory processes in cortical circuits are tightly modulated by dopamine (DA)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    This maturation fails to occur or is abnormal in several different rodent models of schizophrenia, yielding a number of functional and behavioral deficits relevant to the disease.

    “This maturation fails to occur or is abnormal in several different rodent models of schizophrenia, yielding a number of functional and behavioral deficits relevant to the disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    DA is critical for modulating both excitatory glutamate transmission and local inhibition mediated by GABA.

    “DA is critical for modulating both excitatory glutamate transmission and local inhibition mediated by GABA. 4”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] source

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  • May combine two claims.

    Premisereasoning

    Schizophrenia pathophysiology has a complex developmental trajectory because overt symptoms become evident during late adolescence despite earlier events contributing to the disease.

    “Schizophrenia pathophysiology has a complex developmental trajectory because overt symptoms become evident during late adolescence despite earlier events contributing to the disease.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The modulation of excitation-inhibition balance in the PFC and hippocampus by DA matures during adolescence.

    “It has indeed been proposed that the modulation of excitation-inhibition balance in the PFC and hippocampus by DA matures during adolescence.4”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] source

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  • May combine two claims.

    Premisecitation

    Noncompeting NMDA antagonists affect inhibitory interneuron function by altering redox mechanisms, an effect that depends on interleukin 6 and other cytokines.

    “Noncompeting NMDA antagonists affect inhibitory interneuron function by altering redox mechanisms, 74 an effect that depends on interleukin 6 and other cytokines.75”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] source

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    • cites [75] source

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  • May combine two claims.

    Premisecitation

    Adult rats with a NVHL show hyperlocomotion, increased response to novelty, abnormal social behaviors, exaggerated responses to stress, stimulants and NMDA antagonists, and increased liability for addictive behaviors.

    “Behaviorally, adult rats with a NVHL show hyperlocomotion, 39,40 increased response to novelty, 41 abnormal social behaviors, 41 exaggerated responses to stress, stimulants and NMDA antagonists, 39,42 and increased liability for addictive behaviors.43,44”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [39]

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  • May combine two claims.

    Premisecitation

    The prenatal administration of MAM yields adult rats with fewer interneurons expressing PV and loss of high-frequency oscillations.

    “the prenatal administration of MAM yields adult rats with fewer interneurons expressing PV and loss of high-frequency oscillations.38”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] source

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  • May combine two claims.

    Interpretationreasoning

    Increased electrical activity may result in enhanced metabolic demand, which could yield to the higher vulnerability.

    “This increased electrical activity may result in enhanced metabolic demand, which could yield to the higher vulnerability.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Fast-spiking PV positive interneurons present high firing rates and their membrane potential sits at a relatively depolarized value.

  • May combine two claims.

    Premisecitation

    In juvenile rats, D1 agonists increase GABA interneuron firing, whereas D2 agonists have either a weak inhibitory effect or no effect.

    “In juvenile rats, D 1 agonists increase GABA interneuron firing, whereas D 2 agonists have either a weak inhibitory effect or no effect.12,13”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] source

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    • cites [13] source

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  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    The diverse set of possible causes of interneuron dysfunction may have relevance to schizophrenia because the disease likely involves multiple etiologies.

    “The diverse set of possible causes of interneuron dysfunction may have relevance to schizophrenia because the disease likely involves multiple etiologies.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Schizophrenia likely involves multiple etiologies.

  • May combine two claims.

    Premisecitation

    NMDA antagonists increase rat PFC pyramidal cell firing and decrease fast-spiking interneuron firing, and increase glutamate levels.

    “The pioneering work of Bita Moghaddam showed increases in rat PFC pyramidal cell firing and decreases in fast-spiking interneuron firing 32 as well as increase in glutamate levels 33 with these agents”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] source

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    • cites [33] source

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  • May combine two claims.

    Premisecitation

    Recordings in brain slices revealed increased excitability of pyramidal neurons and a deficient activation of fast-spiking GABA interneurons by D2 agonists in the PFC of NVHL rats.

    “Recordings in brain slices revealed increased excitability of pyramidal neurons 52 and a deficient activation of fast-spiking GABA interneurons by D 2 agonists 53 in the PFC of NVHL rats.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] source

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    • cites [53] source

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  • May combine two claims.

    Interpretationown data

    Impaired activation of PFC interneurons by DA is a critical feature of the NVHL model, and the functional consequences of such impairment emerge during adolescence.

    “the data obtained with NVHL rats indicate that impaired activation of PFC interneurons by DA is a critical feature of this model, and the functional consequences of such impairment emerge during adolescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Selective knockout of NR1 subunits in PV+ cortical interneurons in mice yields sensorimotor gating deficits, working memory deficits, hyperlocomotion, enhanced response to stimulants, and other schizophrenia-related phenomena.

    “mice in which NR1 subunits of the NMDA receptor were knocked out selectively in PVþ cortical interneurons yield sensorimotor gating deficits, working memory deficits, hyperlocomotion, enhanced response to stimulants, and many other schizophrenia-related phenomena.23”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] source

      Not checked in the free run.

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

    Interpretationreasoning

    Early deficits in cortical glutamate, GABA, and DA interactions would not become apparent until the periadolescent maturation brings these interactions online.

    “early deficits in cortical glutamate, GABA, and DA interactions would not become apparent until the periadolescent maturation brings these interactions online.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Genetic risk factors may contribute to this scenario both at the presynaptic and postsynaptic level.

    “Genetic risk factors may contribute to this scenario both at the presynaptic and postsynaptic level.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Human neurophysiological studies show neural synchrony during a Gestalt perception task was transiently reduced during late adolescence, an effect that correlated with loss of performance.

    “Human neurophysiological studies are consistent with this idea of a vulnerable period during adolescence, as neural synchrony (a neurophysiological readout of interneuron function) during a Gestalt perception task was transiently reduced during late adolescence, an effect that correlated with loss of performance.77”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Reduced NMDA activation in interneurons induces cytokine expression and redox alterations, and reduced activity of these neurons yields lower levels of parvalbumin.

    “Reduced NMDA activation in this cell population induces cytokine expression and redox alterations, and in the end, the reduced activity of these neurons yields lower levels of parvalbumin.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Available models have advanced the views of pathophysiological mechanisms to a point in which new intervention strategies can be developed with a strong rationale behind.

    “it is clear that the available models have advanced the views of pathophysiological mechanisms to a point in which new intervention strategies can be developed with a strong rationale behind.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    There may be many ways to alter interneuron function that yield disinhibited cortical circuits.

    “There may be many ways to alter interneuron function that yield disinhibited cortical circuits.”
    Quote in the paperNot a substantial claim
23 of 23

  • The paper relies on this without support.

    An important factor in slow progress in schizophrenia research has been the difficulty in reproducing many aspects of the disease in animals.

    “An important factor in such slow progress has been the difficulty in reproducing many aspects of the disease in animals.”

  • The paper relies on this without support.

    The onset of florid symptoms typically occurs during late adolescence.

    “Because the onset of florid symptoms typically occurs during late adolescence”

  • The paper relies on this without support.

    Adolescence is a well-characterized period in rodents.

    “Adolescence is a well-characterized period in rodents.”

  • The paper relies on this without support.

    Rodent adolescence corresponds to human adolescence in ways relevant to schizophrenia.

    “it is critical that schizophrenia-relevant phenomena emerge at a similar developmental stage in animal models.”

  • The paper relies on this without support.

    Animal models of schizophrenia can provide valid insight into human pathophysiological changes.

    “animal work is now providing important insight onto possible pathophysiological changes in the brain.”

  • The paper relies on this without support.

    The timing of emergence of anomalies in animal models should match late adolescence in humans.

    “it is critical that schizophrenia-relevant phenomena emerge at a similar developmental stage in animal models.”

  • The paper relies on this without support.

    The psychotomimetic effects of NMDA antagonists are relevant to schizophrenia pathophysiology.

    “Noncompeting NMDA antagonists have provided us with a possible scenario in which DA alterations are secondary to abnormal information processing in cortical regions.”

  • The paper relies on this without support.

    Fast-spiking PV positive interneurons present high firing rates and their membrane potential sits at a relatively depolarized value.

    “Indeed, fast-spiking PV positive interneurons present high firing rates and their membrane potential sits at a relatively depolarized value.”

  • The paper relies on this without support.

    Schizophrenia likely involves multiple etiologies.

    “because the disease likely involves multiple etiologies.”
9 of 9

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 correct balance of inhibition and excitation seems to be critical for normative executive function, and conversely, disturbance of this balance is thought to be a fundamental component of psychiatric illness.

    “Thus, the correct balance of inhibition and excitation seems to be critical for normative executive function, and conversely, disturbance of this balance is thought to be a fundamental component of psychiatric illness.69, 70”

    From A role for synaptic plasticity in the adolescent development of executive function (2013) · cites this paper as [70]

    The ‘Cortical Disinhibition as a Common Final Pathophysiological Condition for Schizophrenia Models’ section says proper prefrontal inhibition is required for cognitive functions and that disrupted excitatory–inhibitory balance could produce schizophrenia-related symptoms. The Conclusions likewise discuss restoring that balance in schizophrenia. These passages support the link to cognition and schizophrenia, but not the broader claim about psychiatric illness generally; page numbers were not provided. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • E/I balance is tightly maintained in cortical networks and is affected in schizophrenia.

    “Indeed such balance is tightly maintained in cortical networks, and was shown affected in SCZ.144”

    From Are hallucinations due to an imbalance between excitatory and inhibitory influences on the brain? (2016) · cites this paper as [144]

  • In cortical networks, excitatory-inhibitory balance is tightly maintained and appears affected in schizophrenia.

    “Indeed such balance is tightly maintained in cortical networks, and appears to be affected in schizophrenia (O'Donnell, 2011).”

    From What visual illusions teach us about schizophrenia (2014) · cites this paper as O'Donnell, 2011

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. 2007, 144, 1109
  2. Delay, 1955, 168, 318
  3. 1993, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 90, 67
  4. 2010, Biological psychiatry, 69, 431

Cited by

Sorted by citations

Related

Authors
O'Donnell, P.
Venue
Schizophrenia Bulletin
Publisher
Oxford University Press (OUP)
Published
2011-04-19
Volume
37
Issue
3
Pages
484-492
ISSN
  • 0586-7614 (ISSN-L)
  • 1745-1701
DOI
10.1093/schbul/sbr028
PMC
PMC3080677
OpenAlex
W2117561082
Semantic Scholar
76aadaecffd92721a62341530f3ff7ab5efaee63
Cited by
145
References
82
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 15 · 2022: 11 · 2021: 10 · 2020: 7 · 2019: 4 · 2018: 7 · 2017: 11 · 2016: 16 · 2015: 13 · 2014: 16 · 2013: 17 · 2012: 9
FWCI
1.92
Type
journal article
Language
en
Open access
Locations
  • Schizophrenia Bulletin (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Mental Health (R01MH060131, R01 MH60131)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
schizophrenia, cortical disinhibition
MeSH terms
Adolescent, Animals, Cerebral Cortex, Disease Models, Animal, Dopamine, Humans, Neural Pathways, Risk Factors, Schizophrenia, Age of Onset, Adolescent Development

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