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

摘要

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 NR 2B 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 NR 2B protein are significantly decreased in juvenile MAM animals, and the function of NMDAR s is substantially compromised. Both NMDA ‐ mEPSC s and synaptic NMDA ‐ eEPSC s are significantly reduced in prelimbic PFC (pl PFC ). 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 Ch IP ‐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 NR 2B protein and subsequent synaptic dysfunction weakens pl PFC function during development and may underlie early cognitive impairments in SCZ models and patients. Read the Editorial Highlight for this article on page 264 .