Developmental Regulation of H3K27me3 Drives Excitatory Synapse Maturation and Social Behavior

During brain development, chromatin regulation determines how and when genes are transcribed, making sure that the right genes are turned on and the wrong genes are turned off. Previously, we have identified a role for the Jumonji-C lysine-specific histone demethylase Kdm6b in cerebellar granule neurons (CGNs) in mediating the induction of a mature gene expression program. More specifically, this program of gene expression contains a variety of synaptic genes, crucial for the post-synaptic differentiation of CGNs and the overall cerebellar circuit. Consistent with this, we report that neurons without Kdm6b have smaller and less complex dendritic claws, structures that contain most of the synaptic inputs onto the cells. Additionally, we show that proper claw formation is dependent on the enzyme’s catalytic activity. CGNs lacking Kdm6b have increased distribution of excitatory synapses on their smaller claws, suggesting that normally, Kdm6b works to develop these claws so the cells can properly distribute synapses. Interestingly, mice lacking Kdm6b activity show deficits in social novelty and discrimination, highlighting a possible behavioral consequence linked to chromatin misregulation. Whether this aberrant phenotype is specifically due to synaptic defects associated with loss of demethylase activity remains to be resolved. However, these results defined a novel role for Kdm6b in regulating synapse formation and have expanded our knowledge on how chromatin regulation contributes to neuronal maturation and ultimately, social behavior.