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ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior. Specific depletion of Ash1l in forebrain induces similar ASD-associated behavioral defects. While the learning ability remains intact, the discrimination ability of Ash1l mutant mice is reduced. Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period. Dysregulation of synaptic genes is detected in Ash1l mutant brain. Specifically, Eph receptor A7 is downregulated in Ash1l

Background Immediate-early genes (IEGs) have been serving as markers of active neurons for their rapid responses to stimulation. With the development of IEG-EGFP reporters by the GENSAT project, application of the IEGs have been greatly expanded. However, detailed validations for these systems are still lacking, causing trouble in the interpretation of the fluorescence signals. New method In this work, taken Egr1-EGFP transgenic mice as an example, we proposed an improvement for the usage of the Egr1-EGFP reporter system based on detailed validation of its fluorescence signals. Results Firstly, the exogenous EGFP mRNA levels were linearly correlated with the endogenous Egr1 mRNA levels in neurons. Secondly, the 3-hr-changes of the Egr1-EGFP signals before and after the stimulus were positively correlated with the stimulus-induced neuronal activities. Interestingly, persistent neuronal activity patterns in the post-stimulus phase also showed correlation with the stimulus-induced Egr1-EGFP signal changes. Furthermore, enriched environments engaged dramatic neuronal activations, allowing detailed characterization of Egr1-EGFP expression dynamics. Comparison with existing method(s) People used to infer the neuronal activities based on the raw fluorescence signals of IEG-EGFP reporter system, which was strongly obstructed by distinct protein regulation or dynamic properties between the EGFP and the IEGs. We demonstrated a better way for data analysis and experimental design. Conclusions Taken together, this work proves that Egr1-EGFP signal is weakly but significantly correlated to task-induced neural activity and gives detailed characterization of the signal dynamics. It not only provides basis for the understanding of the IEG-EGFP fluorescence signals but also offers instructions for proper experimental design with IEG-EGFP reporter systems.

The formation of long-term memory involves a series of molecular and cellular changes, including gene transcription, protein synthesis and synaptic plasticity dynamics. Some of these changes arise during learning and are subsequently retained throughout life. 'Epigenetic' regulation, which involves DNA methylation and histone modifications, plays a critical role in retaining long-term changes in post-mitotic cells. Accumulating evidence suggests that the epigenetic machinery might regulate the formation and stabilization of long-term memory in two ways: a 'gating' role of the chromatin state to regulate activity-triggered gene expression; and a 'stabilizing' role of the chromatin state to maintain molecular and cellular changes induced by the memory-related event. The neuronal activation regulates the dynamics of the chromatin status under precise timing, with subsequent alterations in the gene expression profile. This review summarizes the existing literature, focusing on the involvement of epigenetic regulation in learning and memory. We propose that the identification of different epigenetic regulators and signaling pathways involved in memory-related epigenetic regulations will provide mechanistic insights into the formation of long-term memory.

Summary Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an in vivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death.

Here we describe a novel mechanism for plasma membrane insertion of the delta opioid receptor (DOR). In small dorsal root ganglion neurons, only low levels of DORs are present on the cell surface, in contrast to high levels of intracellular DORs mainly associated with vesicles containing calcitonin gene-related peptide (CGRP). Activation of surface DORs caused Ca(2+) release from IP(3)-sensitive stores and Ca(2+) entry, resulting in a slow and long-lasting exocytosis, DOR insertion, and CGRP release. In contrast, membrane depolarization or activation of vanilloid and P2Y(1) receptors induced a rapid DOR insertion. Thus, DOR activation induces a Ca(2+)-dependent insertion of DORs that is coupled to a release of excitatory neuropeptides, suggesting that treatment of inflammatory pain should include blockade of DORs.