GABA(A)R-δ-subunit mediates increased GABAergic inhibition in cardiac DMV neurons after high-fat diet.

Activity of cardiac-projecting neurons in the dorsal motor nucleus of the vagus (CVN(DMV)) is vital in cardiac reflexes contributing to maintaining cardiovascular health. However, how this population adapts to metabolic challenges, such as high-fat diet (HFD), is unclear. This study aimed to identify neuroplasticity changes induced by HFD in CVN(DMV). Using whole-cell patch-clamp electrophysiology, we found that 15-day HFD feeding increased tonic, but not phasic, gamma-aminobutyric acid type A (GABA(A)) inhibitory neurotransmission, exclusive to CVN(DMV). Single-cell quantitative reverse-transcription PCR (scRT-qPCR) analysis revealed a higher number of CVN(DMV) expressing GABA(A) receptor δ-subunit (GABA(A)(δ)R) in HFD compared to normal fat diet (NFD). Deletion of GABA(A)(δ)R in ChAT-positive motor neurons abolished HFD-induced increased tonic GABA(A) neurotransmission in CVN(DMV). Altogether, this evidence suggests that CVN(DMV) exhibits early onset HFD-induced increased GABAergic neurotransmission, likely mediated by GABA(A)(δ)R. This increased inhibitory tone could explain previously reported reduced cardiac vagal motor output, thus contributing to poor cardiometabolic health after HFD.