In the present study, postnatal PCI-32765 distributor maternal separation appreciably decreased the association between MeCP2 and the methylated CpG sites via increasing the phosphorylation of serine residue 421 of MeCP2, and subsequently reduced the occupancy of transcriptional factors and altered the histone acetylation and cytosine methylation in the promoter region of Crh. These epigenetic modifications potentially accounted for the upregulation of hippocampal CRH in the rats with postnatal maternal separation. This provided a novel epigenetic mechanism underlying the hippocampal synaptic dysfunction and memory deficiency induced by postnatal maternal deficiency. A number of evidences indicated that CRHR1 signaling predominately mediated CRH-involved modulation of neurotransmission and response to stress. In the central neurons, the primary mode of CRHR1 signaling is through G protein subunit Gsa, which binds to the third intracellular loop of the receptor. Stimulation of CRHR1 signaling results in the activation of intracellular adenylyl cyclase, cyclic AMP and protein kinase A pathway, extracellular signal-regulated kinase signaling, and other signaling pathways. Previous morphological evidence confirmed the localization of CRH in the hippocampal CA1 neurons. CRH, either endogenous peptide released Vismodegib during stress or exogenous peptide, exhibited the effect on hippocampal glutamatergic transmission and memory in the doseand time-dependent manner. Transient release of CRH usually enhanced glutamatergic synaptic strength, via increasing presynaptic glutamate release and/or postsynaptic excitability, and primed HFS-induced LTP in hippocampal neurons, and improved the acquisition and retention in several hippocampus-dependent tasks. However, sustained exposure to CRH, via CRHR1, substantially reduced glutamatergic synaptic plasticity, induced the loss of spines, lowered the total dendritic length and complexity in hippocampal neurons, and impaired learning and memory in the rodents. Recently a reduction of hippocampal cell adhesion molecule nectin-3, which resulting from the hyperactivity of CRH- CRHR1 signaling, was reported in the rodents with exposure to early-life stress exposure, and recovery of hippocampal nectin-3 expression rescued the detrimental effects of early-life stress on memory and spine density in adulthood. The present study revealed that postnatal maternal separation induced the longlasting upregulation of hippocampal CRH, and blockade of CRHCRHR1 signaling significantly improved the hippocampal synaptic plasticity and performance in the memory behavioral tests in the modeled rats. These results indicated the critical role of upregulation of CRH-CRHR1 signaling in the pathogenesis of memory deficiency-induced by postnatal maternal separation. Series of evidences demonstrated that environmental enrichment substantially improved the glutamatergic synaptic plasticity in the central neurons and cognitive performance in the rodents. Environmental enrichment significantly increased dendritic branching and length, the number of dendritic spines and the size of synapses in hippocampal and cortex neurons. It also enhanced the neurogenesis and the integration of these newly born cells into functional circuits in the dentate gyrus. Enrichment induced appreciable redistribution of the glutamate receptor subunits.