Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes
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Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40-50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.
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The choroid plexus, acting through cerebrospinal fluid, may regulate critical-period plasticity generally, including in the amygdala, auditory cortex, and prefrontal cortex, which have critical periods that are shifted or shorter than that of primary visual cortex.
“Thus, one striking implication is that the choroid plexus, via the CSF, may be a general regulator of CP plasticity, including the amygdala (Gogolla et al., 2009), auditory (Barkat et al., 2011) or prefrontal cortex (Belforte et al., 2010; Yang et al., 2012) – structures with shifted or shorter critical periods than V1.”
From Choroid-Plexus-Derived Otx2 Homeoprotein Constrains Adult Cortical Plasticity (2013) · cites this paper as Belforte et al., 2010
Postnatal deletion of the NR1 subunit of NMDARs in a subpopulation of interneurons including most parvalbumin interneurons leads to parvalbumin and GAD67 expression deficits along with oxidative stress in parvalbumin interneurons.
“When applied during postnatal development, a deletion of the NR1 subunit of NMDARs in a subpopulation of interneurons (including most PVI) leads to parvalbumin and GAD67 expression deficit along with oxidative stress in PVI (Belforte et al., 2010; Jiang et al., 2013).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Belforte et al., 2010
Deregulation of AMPA and/or NMDA receptors in inhibitory interneurons and dysregulation of E/I balance could be responsible for the cognitive and behavioural abnormalities characteristic of a range of neurodegenerative and psychiatric disorders.
“In particular, the deregulation of AMPA and/or NMDA receptors in inhibitory interneurons and the dysregulation of E/I balance could be responsible for the cognitive and behavioural abnormalities characteristic of a range of neurodegenerative and psychiatric disorders (Belforte et al. 2010; Bozzi et al. 2018; Caputi et al. 2012; Foss-Feig et al. 2017; Fuchs et al. 2007; Korotkova et al. 2010; Lewis”
From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Belforte et al. 2010
Selective ablation of NMDARs later in development in PV-positive interneurons alters theta and gamma oscillations and impairs spatial and short- and long-term memory.
“Selective ablation of NMDARs later in development in PV-positive interneurons alters theta and gamma oscillations with consequent impairments in spatial and short- and long-term memory tests, indicating a critical role for NMDARs in PV-interneuron-mediated circuit entrainment (82, 599).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [82]
Loss of NMDARs in PV-containing interneurons at early postnatal ages triggers behavioral deficits associated with schizophrenia.
“Loss of NMDARs in PV-containing interneurons at early postnatal ages triggers behavioral deficits associated with schizophrenia including psychomotor agitation, anhedonia, reduced pre-pulse inhibition of acoustic startle, deficits in nesting/mating, and social withdrawal (82), supporting an NMDAR hypofunction theory of schizophrenia (for reviews, see Refs. 234, 235).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [82]
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”
From Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models (2011) · cites this paper as [23]
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- Authors
- Belforte, J. E., Zsiros, V., Sklar, E. R., Jiang, Z., Yu, G., Li, Y., Quinlan, E. M., & Nakazawa, K.
- Affiliations
- National Institutes of Health (US)
- National Institute of Mental Health (US)
- University of Alabama at Birmingham (US)
- University of Maryland, College Park (US)
- Corresponding author
- Nakazawa, Kazu
- Venue
- Nature Neuroscience
- Published
- 2009-11-15
- Volume
- 13
- Issue
- 1
- Pages
- 76-83
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2797836
- OpenAlex
- W2102092558
- Cited by
- 752
- References
- 49
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 24 · 2023: 35 · 2022: 29 · 2021: 48 · 2020: 32 · 2019: 39 · 2018: 42 · 2017: 41 · 2016: 59 · 2015: 83 · 2014: 49 · 2013: 67 · 2012: 61
- FWCI
- 35.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Conicet (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health
- National Institute of Mental Health (ZIAMH002895)
- National Institute of Neurological Disorders and Stroke (R21NS065273)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- NMDA receptor, NR1 subunit, GABAergic dysfunction, schizophrenia, cortical excitatory neurons, glutamic acid decarboxylase 67, parvalbumin, social isolation stress, prepulse inhibition, social memory, working memory, anhedonia, anxiety, neuronal synchronization, mouse model
- MeSH terms
- Protein Phosphatase Inhibitory Proteins, Action Potentials, Analysis of Variance, Animals, Animals, Newborn, Cerebral Cortex, Disease Models, Animal, Exploratory Behavior, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Hyperkinesis, Interneurons, Limbic System, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neural Pathways, Parvalbumins, Proteins, RNA, Messenger, Schizophrenia, Social Isolation, Receptors, N-Methyl-D-Aspartate, Gene Expression Regulation, Developmental, Statistics, Nonparametric, Recognition, Psychology, Mice
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