PKCδ mediates high-fat diet-induced increased tonic GABA _A receptor current in cardiac vagal motor neurons in the DMV

Consumption of high fat diet (HFD) is linked to reduced cardiac vagal motor output, a main contributor to progression of cardiovascular disease. HFD for 15 days increases extrasynaptic or tonic gamma aminobutyric acid (GABA) current in cardiac projecting neurons in the dorsal motor nucleus of the vagus (CVN ^DMV ), which contributes to dampening cardiac parasympathetic output. However, the mechanism underlying this increased inhibition is unknown. Here, we hypothesize that increased activity of protein kinase C δ isoform (PKCδ) enhances tonic GABA current in CVN ^DMV after HFD. Whole-cell patch-clamp recording of retrogradely labeled CVN ^DMV demonstrated that pan inhibition of PKC activity with GFX, and isoform specific inhibition of PKCδ with rottlerin normalize 15-day HFD-induced increases in tonic GABA current, suggesting that PKCδ mediates enhanced tonic inhibition. This effect persisted in the presence of dynasore, a clathrin-mediated endocytosis blocker, indicating that the normalization effect of PKCδ inhibition on tonic current in HFD is likely independent of clathrin-mediated endocytosis. Furthermore, no differences in PKCδ mRNA or protein expression were observed between NFD and HFD, suggesting a post-translational mechanism underpinning increased tonic GABA current after 15 days of HFD. Altogether, this study provides evidence that HFD-induces increased PKCδ activity, but not expression, leading to increased tonic GABAergic inhibition in CVN ^DMV . This increase PKCδ activity could explain the cardiac vagal motor output dampening in CVD and be developed into treatments targeting PKCδ for CVD.