Spontaneous Axonal ER Ca2+ Waves Mediate A Shift From Action Potential-Dependent to Independent Glutamate Release in the YAC128 HD-Model

Mackay, J. P.; Buren, C.; Smith-Dijak, A. I.; Koch, E. T.; Zhang, P.; Schmidt, M.; Fung, E.; Nassrallah, W. B.; Hayden, M. R.; Raymond, L. A.

doi:10.1101/2020.01.31.929299

bioRxiv · 10.1101/2020.01.31.929299

Spontaneous Axonal ER Ca2+ Waves Mediate A Shift From Action Potential-Dependent to Independent Glutamate Release in the YAC128 HD-Model

Mackay, J. P.·Buren, C.·Smith-Dijak, A. I.·Koch, E. T.·Zhang, P.·Schmidt, M.·Fung, E.·Nassrallah, W. B.·Hayden, M. R.·Raymond, L. A.

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Abstract

Action potential-independent (miniature) neurotransmission occurs at all chemical synapses, but remains poorly understood, particularly in pathological contexts. Spontaneous release of Ca2+ from the axonal endoplasmic reticulum (ER) is thought to facilitated miniature neurotransmission, and aberrant ER Ca2+ handling is notably implicated in the progression of Huntingtons disease (HD) and other neurodegenerative diseases. Here, we report elevated glutamate-mediated miniature synaptic event frequencies in YAC128 (HD-model) cortical neurons, which pharmacological experiments suggest is mediated by enhanced spontaneous ER Ca2+ release. Calcium imaging using an axon-localized sensor revealed slow action potential (AP)-independent axonal Ca2+ waves, which were more common in YAC128 cortical neurons. Conversely, spontaneous axonal ER Ca2+ release was associated with reduced AP-dependent axonal Ca2+ events and consequent glutamate release. Together, our results suggest spontaneous release of axonal ER Ca2+ stores oppositely regulates activity-dependent and -independent neurotransmitter release in HD, with potential implications for the fidelity and plasticity of cortical excitatory signaling.

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Mackay, J. P., Buren, C., Smith-Dijak, A. I., Koch, E. T., Zhang, P., Schmidt, M., Fung, E., Nassrallah, W. B., Hayden, M. R., Raymond, L. A.. 2020-01-31. Spontaneous Axonal ER Ca2+ Waves Mediate A Shift From Action Potential-Dependent to Independent Glutamate Release in the YAC128 HD-Model. https://doi.org/10.1101/2020.01.31.929299

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