Unraveling the Role of Neurexin 3 in Alcohol Use Disorder: Insights from Primate and Rodent Models

About This Grant

Project Summary This interdisciplinary project addresses the pressing public health challenge of alcohol use disorder (AUD). AUD affects approximately 14% of adults in the United States alone, with profound societal and individual detrimental consequences. Despite its prevalence, effective treatments for AUD are limited, highlighting the urgent need for a better understanding of the underlying molecular mechanisms of this disorder. This project investigates the role of neurexin 3 (NRXN3) in AUD using rhesus macaque and mouse models. Our laboratory has shown that NRXN3, a presynaptic transmembrane protein, is downregulated in the prefrontal cortex of high ethanol consuming non-human primates. Given the central role of this protein in synaptic transmission and plasticity, processes known to underlie AUD-related behaviors, investigating its role in mediating the effects of alcohol in brain function is paramount. However, the specific role of NRXN3 in AUD remains poorly understood, with only a handful of published GWAS studies linking single nucleotide polymorphisms with different risk propensities for addiction. Here, we aim to elucidate the NRXNs' landscape in the cortex following chronic ethanol use and protracted abstinence, with particular focus on a specific transcript/isoform, Nrxn3β, and its role in synaptic plasticity. It also explores manipulating Nrxn3β transcripts in one of the major inhibitory neurons in the cortex, parvalbumin (PV) neurons, to modulate excitatory outputs to reward and motor centers and reduce ethanol intake. By employing cutting-edge molecular profiling techniques, advanced immunohistological analyses, and in vivo manipulation, we will examine changes in Nrxns’ expression and excitatory/inhibitory synaptic properties in key brain regions implicated in AUD, such as the prefrontal cortex. This research holds significant intellectual significance as it seeks to advance our understanding of the neurobiological basis of AUD and identify novel therapeutic targets. By uncovering the precise mechanisms through which Nrxn3β influences synaptic plasticity and alcohol-related behaviors, we aim to inform the development of targeted interventions to mitigate the adverse effects of AUD and improve treatment outcomes for affected individuals.