Triglycerides are an important fuel reserve for synapse function in the brain

Proper fueling of the brain is critical to sustain cognitive function but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2, a genetic driver of complex hereditary spastic paraplegia, or of the mitochondrial lipid transporter, CPT1, leads to rapid onset of torpor in mice. These data indicate that in-vivo neurons are likely constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons electrical silencing or blocking DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support likely play a critical role in supporting neuron function in-vivo.