Post-translational modifications of histones, including methylation, are critical for regulating gene expression and maintaining homeostasis. In neurons, dysregulation of histone methylation is associated with neurodevelopmental disorders such as autism spectrum disorders (ASD). SET Domain Containing 2, histone lysine methyltransferase (SETD2) that methylates histone H3 at lysine 36 (H3K36) and is the primary methyltransferase for trimethylating H3K36 in human (H3K36me3). SETD2 is unique among histone methyltransferase in that it directly binds RNA Pol ll and deposits H3K36me3 co-transcriptionally. H3K36me3 primarily involved in transcriptional regulation but can also regulate alternative splicing. Haploinsufficiency of SETD2 is responsible for Sotos-like overgrowth syndrome, characterized by obesity, macrocephaly, intellectual disability, autism, and epilepsy. SETD2 is also considered a “high confidence” ASD-risk gene in the SFARI gene database (https://gene.sfari.org/). Little is known of the role of SETD2 in the brain. There is also little known of the role of histone methylation, specifically H3K36me3, in postnatal developing brain. To address these gaps in knowledge, I made a mouse with conditional deletion of Setd2 postnatally (~P8) in excitatory forebrain neurons using the BAC-CaMKIIα Cre line. Acute slices of somatosensory neocortex from young, 3rd postnatal week, Setd2 heterozygous mice (SetD2 cHet) have increased circuit excitability, as measured by the duration and power of persistent activity, or UP, states. We find the same “long UP state” phenotype in the mouse model of Fragile X Syndrome (Fmr1 KO), the most common monogenic cause of ASD. In both Setd2 cHet and Fmr1 KO long duration UP states are rescued by a negative allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), as well as protein synthesis inhibitors. This suggests hyperactivation of the mGluR5 signaling pathway to protein synthesis with Setd2 deletion and a point of convergence of these two ASD-risk genes. Fmr1 encodes Fragile X mRNA ribonucleoprotein (FMRP), an RNA binding protein, that regulates translation of mRNAs associated with ASD. I hypothesize that loss of SETD2 leads to altered expression of FMRP and/or alternative splicing of genes that are also regulated by FMRP at the translation level. Specifically, I hypothesize that these commonly regulated genes may encode components of protein synthesis machinery, proteins that regulate synaptic, neuronal and circuit function and/or mGluR5, its interacting partners or effectors. To test this hypothesis. in Aim 1 I will identify genes with altered H3K36me3 marks, expression and splicing in Setd2 cHet cortex and determine their overlap with FMRP regulated mRNAs, or pathways. In Aim 2, I will test candidate mGluR5-regulated, neuronal and synaptic mechanisms for circuit hyperexcitability in Setd2 cHet mice. In Aim 3, I will determine if there are altered mGluR5 complexes and signaling to protein synthesis in th...