Ash1L Mediates Neuronal Activity-dependent Regulation Of Neurexin-1?

Activity-dependent gene expression is closely associated with neuronal plasticity.The expression of many genes are regulated by neuronal activity,including immediate-early genes,such as Egr1,Fos and Npas4,and the synaptic proteins encoding genes,such as Bdnf,which promotes neuronal survival and modulates synaptic activity.Many studies have characterized the programs of gene transcription that are altered in response to activity stimulus.The basic question of transcriptional and epigenetic mechanisms remain unanswered.Neurexin-1?(Nrxn1?)is the presynaptic adhesion protein with the function of synaptic development and transmission.The mutants of this gene have been widely observed in many neurological diseases,including schizophrenia,autism spectrum disorders(ASDs)and epilepsy.However,the regulation mechanism underlying Nrxn1? expression is still unclear.Here,we report that the expression of Nrxn1? undergoes activity-dependent long-term repression.By a screening assay using synthetic zinc finger protein(GST-ZFP-pnrxn1?)to pull-down the proteins enriched near the Nrnx1? promoter region in vivo,we identify that Ash1 L,a histone methyltransferase,is enriched in the Nrnx1? promoter and essential for the activity-dependent repression of Nrxn1?.Neuronal activity triggered binding of Ash1 L to the Nrxn1? promoter and enriched the histone marker H3K36me2 at the promoter region in primary cortical neuron cultures.Knockout of Ash1 L in neurons totally abolished the activity-dependent repression of Nrxn1?.The transcription of Ash1 L in hippocampus was relatively high,comparing to other brain areas.Ash1L+/-mice exhibited up-regulation of Nrxn1? m RNA,and reduction of H3K36me2 at the Nrxn1? promoter region in hippocampus,corresponding the increased synapse density in the CA1 striatum radiatum.Ash1L+/-mice demonstrated normal contextual fear learning and memory acquisition.The memory was unstable,and susceptible to interference.In fear-discrimination task,Ash1L+/-mice were impaired in their ability to distinguish between two similar contexts.Taken together,we identified a novel process of activity-dependent transcriptional repression in neurons and revealed that Ash1 L mediates the long-lasting repression of Nrxn1?,implicating an important role of epigenetic modification in brain functioning.