Neuronal autophagy controls excitability via ryanodine receptor–mediated regulation of calcium-activated potassium channel function

Abstract

Glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures and promoting epileptogenesis. Recent data suggest that altered autophagy can contribute to the occurrence of epilepsy. We examined the role of autophagy in neuronal physiology by generating knockout mice conditionally lacking the essential autophagy protein ATG5 in glutamatergic neurons. We demonstrate that conditional genetic blockade of neuronal autophagy results in action potential narrowing, axonal hyperexcitability, and an increase in kainate-induced epileptiform bursts ex vivo, indicative of a lower threshold for the induction of epileptic seizures. Neuronal hyperexcitability in hippocampal slices from conditional ATG5 knockout mice is due to elevated activity of the large conductance calcium-activated potassium channel BKCa downstream of calcium influx via the endoplasmic reticulum (ER)-localized calcium channel ryanodine receptor (RYR). Consistently, pharmacological blockade of RYR or BKCa function rescued hyperexcitability and reduced the frequency of kainate-induced epileptiform bursts in ATG5 cKO brain slices. Our findings reveal a physiological role for neuronal autophagy in the regulation of neuronal excitability via the control of RYR-mediated calcium release, and thereby, calcium-activated potassium channel function in the mammalian brain.