Novel target identification using single cell sequencing and electrophysiology of cardiac sympathetic neurons in disease

Abstract

AbstractThe activity of cardiac sympathetic nerves from the stellate ganglia is increased in many cardiovascular diseases contributing to the pathophysiology, however the mechanisms underlying this are unknown. Moreover, clinical studies show their surgical removal is an effective treatment, despite the biophysical properties of these neurons being largely unstudied. Here we demonstrate that stellate ganglia neurons from prehypertensive spontaneously hypertensive rats are hyperactive and describe in detail their electrophysiological phenotype guided by single cell RNA-sequencing, molecular biology and perforated patch-clamp to uncover the underlying mechanism. The expression of key transcripts was confirmed in human stellate ganglia. We further demonstrate the contribution of a plethora of ion channels to stellate ganglia neuronal firing, and show that hyperexcitability was curbed by M-current activators, non-selective sodium current blockers or inhibition of Nav1.1-1.3, Nav1.6 or INaP. These findings have implications for target discovery to reduce cardiac sympathetic activity without resorting to surgery.