Abstract
<title>Abstract</title> <p> <underline> <bold>Background</bold> </underline> : Neurexins are presynaptic cell adhesion molecules critical in regulating synaptic adaptations. Although single nucleotide polymorphisms mapping to <italic>NRXN3</italic> have been linked to substance use disorders, the specific alterations to <italic>NRXN3</italic> ’s transcript/protein isoform diversity that accompany chronic ethanol use remain unknown. <underline> <bold>Methods</bold> </underline> : Unbiased RNAseq and transcript-specific qPCR were conducted on the dorsolateral prefrontal cortex (dlPFC) of male and female rhesus macaques that remained alcohol-naïve (controls) or self-administered ethanol for 12 months. Immunofluorescence (IF) was used to measure the levels of Nrxn3 isoforms across different cell types in the prelimbic cortex (PLC) of mice following chronic ethanol exposure. <underline> <bold>Results</bold> </underline> : Transcriptome and pathway analyses identified numerous differences in gene expression enriched in interconnected biological networks relevant for synaptic function. <italic>NRXN3,</italic> which was downregulated primarily in female macaques, was identified as a highly connected and central molecule involved in many of these networks. Further evaluation of the different <italic>NRXN3</italic> isoforms demonstrated exclusive downregulation of the short transcript <italic>NRXN3β</italic> across species, that was accompanied by a downregulation of two of its postsynaptic binding partners, neuroligin 2 and <italic>β</italic> -dystroglycan. This downregulation occurred in parvalbumin interneurons and excitatory neurons of the PLC of mice following chronic exposure, although in a sex-specific manner. <underline> <bold>Conclusions:</bold> </underline> Our research provides significant insights into the complex adaptations of NRXN3, and its binding partners, by chronic ethanol within different cell types of the PFC/PLC. We hypothesize these changes are modulating synaptic plasticity in parvalbumin interneurons and excitatory neurons. </p>