Synapse-associated astrocyte mitochondria stabilize motor circuits to prevent excitotoxicity

Abstract

ABSTRACTEarly stages of the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS) are characterized by motor neuron hyperexcitability. During this phase, peri-synaptic astrocytes are neuroprotective. When reactive, loss of wild-type astrocyte functions results in excitotoxicity. How astrocytes stabilize motor circuit function in early-stage ALS is poorly understood. Here, we used Drosophila motor neurons to define the role of astrocyte-motor neuron metabolic coupling in a model of ALS: astrocyte knockdown of the ALS-causing gene tbph/TARDBP. In wild-type, astrocyte mitochondria were dynamically trafficked towards active motor dendrites/synapses to meet local metabolic demand. Knockdown of tbph in astrocytes resulted in motor neuron hyperexcitability, reminiscent of early-stage ALS, which was met with a compensatory accumulation of astrocyte mitochondria near motor dendrites/synapses. Finally, we blocked mitochondria-synapse association in tbph knockdown animals and observed locomotor deficits and synapse loss. Thus, synapse-associated astrocyte mitochondria stabilize motor circuits to prevent the transition from hyperexcitability to excitotoxicity.