Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals

Abstract

The human brain is a uniquely vulnerable organ as interruption in fuel supply leads to acute cognitive impairment on rapid time scales. The reasons for this vulnerability are not well understood, but nerve terminals are likely loci of this vulnerability as they do not store sufficient ATP molecules and must synthesize them on-demand during activity or suffer acute degradation in performance. The requirements for on-demand ATP synthesis however depends in part on the magnitude of resting metabolic rates. We show here that, at rest, synaptic vesicle (SV) pools are a major source of presynaptic basal energy consumption. This basal metabolism arises from SV-resident V-ATPases compensating for a hidden resting H+ efflux from the SV lumen. We show that this steady-state H+ efflux is 1) mediated by vesicular neurotransmitter transporters, 2) independent of the SV cycle, 3) accounts for ~half of the resting synaptic energy consumption and 4) contributes to nerve terminal intolerance of fuel deprivation. O_LINerve terminals consume large amounts of ATP even at rest C_LIO_LIA large fraction of the resting metabolic burden arises from the V-ATPase C_LIO_LISteady-state V-ATPase activity is driven by a synaptic vesicle H+ leak C_LIO_LIThis H+ leak is mediated vesicular neurotransmitter transporters C_LI