Perineuronal Net and Inhibitory Synapse Remodeling on Striatal Fast-Spiking Interneurons by Chronic Alcohol Exposure

BACKGROUND: Alcohol use disorder is characterized by persistent drinking in the face of negative consequences. Such inflexible drinking requires dorsolateral striatum fast-spiking interneurons, which comprise approximately 1% of all striatal neurons. How chronic ethanol exposure affects fast-spiking interneuron physiology is poorly understood. METHODS: We exposed adult male and female mice to chronic intermittent ethanol and examined synaptic transmission onto dorsolateral striatum fast-spiking interneurons. RESULTS: We discovered that chronic ethanol exposure induced a dramatic loss of GABAergic (gamma-aminobutyric acidergic), but not glutamatergic, synapses onto dorsolateral striatum fast-spiking interneuron somata and proximal dendrites where perineuronal nets (PNNs), a subdivision of the extracellular matrix, are enriched. We found that chronic ethanol exposure degraded these PNNs and that enzymatically degrading PNNs similarly reduced GABAergic transmission onto dorsolateral striatum fast-spiking interneurons. Modeling the effect of alcohol, we found that silencing extrinsic GABAergic projections to the dorsolateral striatum increased voluntary ethanol consumption. CONCLUSIONS: These data suggest that chronic alcohol exposure remodels PNNs and inhibitory synapses on fast-spiking interneurons to facilitate alcohol drinking.