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Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia.

ABSTRACT: Schizophrenia (SCZ) is characterized not only by psychosis, but also by working memory and executive functioning deficiencies, processes that rely on the prefrontal cortex (PFC). Because these cognitive impairments emerge prior to psychosis onset, we investigated synaptic function during development in the neurodevelopmental methylazoxymethanol (MAM) model for SCZ. Specifically, we hypothesize that N-methyl-D-aspartate receptor (NMDAR) hypofunction is attributable to reductions in the NR2B subunit through aberrant epigenetic regulation of gene expression, resulting in deficient synaptic physiology and PFC-dependent cognitive dysfunction, a hallmark of SCZ. Using western blot and whole-cell patch-clamp electrophysiology, we found that the levels of synaptic NR2B protein are significantly decreased in juvenile MAM animals, and the function of NMDARs is substantially compromised. Both NMDA-mEPSCs and synaptic NMDA-eEPSCs are significantly reduced in prelimbic PFC (plPFC). This protein loss during the juvenile period is correlated with an aberrant increase in enrichment of the epigenetic transcriptional repressor RE1-silencing transcription factor (REST) and the repressive histone marker H3K27me3 at the Grin2b promoter, as assayed by ChIP-quantitative polymerase chain reaction. Glutamate hypofunction has been a prominent hypothesis in the understanding of SCZ pathology; however, little attention has been given to the NMDAR system in the developing PFC in models for SCZ. Our work is the first to confirm that NMDAR hypofunction is a feature of early postnatal development, with epigenetic hyper-repression of the Grin2b promoter being a contributing factor. The selective loss of NR2B protein and subsequent synaptic dysfunction weakens plPFC function during development and may underlie early cognitive impairments in SCZ models and patients. Read the Editorial Highlight for this article on page 264.

SUBMITTER: Gulchina Y

PROVIDER: S-EPMC5653427 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia.

Gulchina Yelena Y Xu Song-Jun SJ Snyder Melissa A MA Elefant Felice F Gao Wen-Jun WJ

Journal of neurochemistry 20170905 3

Schizophrenia (SCZ) is characterized not only by psychosis, but also by working memory and executive functioning deficiencies, processes that rely on the prefrontal cortex (PFC). Because these cognitive impairments emerge prior to psychosis onset, we investigated synaptic function during development in the neurodevelopmental methylazoxymethanol (MAM) model for SCZ. Specifically, we hypothesize that N-methyl-D-aspartate receptor (NMDAR) hypofunction is attributable to reductions in the NR2B subun ...[more]

PMID: 28628228

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Project description:Hallucinations, a hallmark of psychosis, can be induced by the psychotomimetic N-methyl-D-aspartic acid (NMDA) receptor antagonists, ketamine and phencyclidine (PCP), and are associated with hypersynchronization in the ?-frequency band, but it is unknown how reduced interneuron activation associated with NMDA receptor hypofunction can cause hypersynchronization or distorted perception. Low-frequency ?-oscillations (LF?) and high-frequency ?-oscillations (HF?) serve different aspects of perception. In this study, we test whether ketamine and PCP affect the interactions between HF? and LF? in the rat visual cortex in vitro. In slices of the rat visual cortex, kainate and carbachol induced LF? (? 34 Hz at 32°C) in layer V and HF? (? 54 Hz) in layer III of the same cortical column. In controls, HF? and LF? were independent, and pyramidal neurons recorded in layer III were entrained by HF?, but not by LF?. Sub-anesthetic concentrations of ketamine selectively decelerated HF? by 22 Hz (EC(50)=2.7 ?M), to match the frequency of LF? in layer V. This caused phase coupling of the two ?-oscillations, increased spatial coherence in layer III, and entrained the firing of layer III pyramidal neurons by LF? in layer V. PCP similarly decelerated HF? by 22 Hz (EC(50)=0.16 ?M), causing cross-layer phase coupling of ?-oscillations. Selective NMDA receptor antagonism, selective NR2B subunit-containing receptor antagonism, and reduced D-serine levels caused a similar selective deceleration of HF?, whereas increasing NMDA receptor activation through exogenous NMDA, D-serine, or mGluR group 1 agonism selectively accelerated HF?. The NMDA receptor hypofunction-induced phase coupling of the normally independent ?-generating networks is likely to cause abnormal cross-layer interactions, which may distort perceptions due to aberrant matching of top-down information with bottom-up information. If decelerated HF? and subsequent cross-layer synchronization also underlie pathological psychosis, acceleration of HF? could be the target for improved antipsychotic therapy.

Dataset Information

Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia.

Publications

Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia.

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