Wisner, S. R. | bioRxiv Science

bioRxiv2025

The combination of elevated neuronal activity and mitochondrial damage induces Pink1-dependent mitophagy in axons

Mitochondria are critical for synaptic function. At the synapse, mitochondria produce ATP and buffer calcium, both of which are required for synapse function. Defects in mitochondrial maintenance are linked to neurodegenerative disease, yet we know little about what regulates the need for mitophagy at the synapse. We assessed the impact of neuron type, activity, and mitochondrial damage on mitophagy rate in axons of larval zebrafish. Using electron and confocal microscopy, we show that mitophagy occurs in the axon terminal of postsynaptic sensory neurons and presynaptic motor neurons at similar rates. Increasing neuronal activity or mitochondria damage does not impact the amount of mitophagy in axons. Only by combining neuronal activity and mitochondrial damage does the rate of mitophagy increase in the axon and this increase requires Pink1. Together, our data support a model in which increased mitophagic demand in axons is rare and uniquely sensitive to Pink1 disruption.

neuroscience↗

bioRxiv2023

A non-conducting role of the Cav1.4 Ca2+ channel drives homeostatic plasticity at the cone photoreceptor synapse

In congenital stationary night blindness type 2 (CSNB2)--a disorder involving the Cav1.4 (L-type) Ca2+ channel--visual impairment is mild considering that Cav1.4 mediates synaptic release from rod and cone photoreceptors. Here, we addressed this conundrum using a Cav1.4 knockout (KO) mouse and a knock-in (G369i KI) mouse expressing a non-conducting Cav1.4. Surprisingly, Cav3 (T-type) Ca2+ currents were detected in cones of G369i KI mice and Cav1.4 KO mice but not in cones of wild-type mouse, ground squirrel, and macaque retina. Whereas Cav1.4 KO mice are blind, G369i KI mice exhibit normal photopic (i.e., cone-mediated) visual behavior. Cone synapses, which fail to form in Cav1.4 KO mice, are present, albeit enlarged, and with some errors in postsynaptic wiring in G369i KI mice. While Cav1.4 KO mice lack evidence of cone synaptic responses, electrophysiological recordings in G369i KI mice revealed nominal transmission from cones to horizontal cells and bipolar cells. In CSNB2, we propose that Cav3 channels maintain cone synaptic output provided that the nonconducting role of Cav1.4 in cone synaptogenesis remains intact. Our findings reveal an unexpected form of homeostatic plasticity that relies on a non-canonical role of an ion channel.

neuroscience↗