Perineuronal net and inhibitory synapse remodeling on striatal fast-spiking interneurons by chronic alcohol exposure
Patton MS, Sheats SH, Wulff AB, McKeon PN, VanRyzin JW, Patton MH, Heckman M, Siclair AN, Iffland PH, & Mathur BN. Biological Psychiatry, 2026.
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.
