NMDA receptors (NMDARs) are critical to synaptogenesis, formation of neural circuitry and to higher cognitive functions. A hallmark feature of NMDARs is a developmental switch in receptor phenotype from primarily GluN2B- to GluN2A-containing during postnatal brain development. Although the developmental switch in NMDARs has been an area of intense interest for nearly two decades, mechanisms that regulate the switch are, as yet, unclear. REST (also known as NRSF) is a gene silencing factor that is widely expressed in embryogenesis and actively represses >2000 predicted neuronal genes important to synaptic plasticity including the NMDAR subunit GluN2B. Polycomb repressive proteins are gene-silencing factors that coordinate with REST to silence > 500 neuron-specific target genes1. Our recent discovery that REST is activated in hippocampal neurons and silences GluN2B at hippocampal synapses during normal postnatal development documents a role for REST in the switch in NMDAR phenotype. Our finding that maternal deprivation early in life blocks activation of REST and the NMDAR switch underscores the clinical relevance of our work. Our recent findings identify a role for ?-TrCP, a key component of the ubiquitin-based proteasomal pathway and known binding partner of REST, in the transient rise in REST during postnatal neurons. The central hypothesis driving the proposed research is that a decline in ?-TrCP stabilizes REST, which together with the polycomb protein EZH2, promotes epigenetic remodeling and the switch in synaptic NMDARs during the 'critical period', a window of heightened plasticity, in the second week postnatal. We seek to test this hypothesis in the following SPECIFIC AIMS: 1. Identify the mechanism by which REST is activated in postnatal neurons and drives the developmental switch in synaptic NMDARs. Experiments will examine 1) the ability of ?-TrCP to negatively regulate REST in postnatal neurons; 2) the ability of a decline in ?-TrCP abundance to drive the developmental switch in synaptic NMDAR phenotype; 3) the ability of DDX3 and CK1 to promote binding of ?-TrCP to REST in differentiated neurons; 4) the impact of maternal deprivation on DDX3, CK1 and ?-TrCP in postnatal development; 5) the ability of `unregulated REST' (CK1/?-TrCP resistant) and/or shRNA to GluN2B to rescue the synaptic NMDAR phenotype and cognition in maternally-deprived animals. 2. Document a role for polycomb repressive proteins in the developmental switch in NMDARs. Experiments will examine 1) recruitment of EZH2 to the grin2b promoter in postnatal neurons 2) the impact of shRNA to EZH2 on enrichment of H3K27me3, a strong repressive mark, and the NMDAR switch; 3) the impact of maternal deprivation on EZH2, enrichment of EZH2 at the grin2b promoter, and cognition; 4) the ability of communal nesting and other enrichment strategies to restore the synaptic NMDAR phenotype and cognition in maternally-deprived animals. Findings from these studies are expected to enhance our understanding of NMDAR function, as it pertains to memory, synaptic stabilization, brain development and cognitive information flow and how adverse experience in the form of maternal deprivation acts via epigenetic remodeling to alter synaptic function.
NMDARs (N-methyl-D-aspartate receptors) mediate excitatory transmission and are critical to synaptogenesis, formation of neural circuitry and to higher cognitive functions such as learning and memory. A hallmark feature of NMDARs is a developmental switch in receptor subunit composition from primarily NR2B- to NR2A containing during postnatal brain development. The proposed research will identify mechanisms by which epigenetic modifications alter synaptic NMDAR properties during normal and abnormal brain development. Adverse experience in the form of maternal deprivation during the first week of postnatal life has a profound and enduring impact on development and prevents acquisition of the mature NMDAR phenotype at hippocampal synapses. This is significant in that early childhood adversity (maternal deprivation, abuse, neglect, and loss) is a known environmental risk factor in neuropsychiatric disorders such as schizophrenia.
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