Axonal ER Ca ²⁺ Release Enhances Miniature, but Reduces Activity-Dependent Glutamate Release in a Huntington Disease Model

Action potential-independent (miniature) neurotransmission occurs at all chemical synapses, but remains poorly understood, particularly in pathological contexts. Spontaneous release of Ca ²⁺ from the axonal endoplasmic reticulum (ER) is thought to facilitated miniature neurotransmission, and aberrant ER Ca ²⁺ handling is notably implicated in the progression of Huntington’s 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 Ca ²⁺ release. Calcium imaging using an axon-localized sensor revealed slow action potential (AP)-independent axonal Ca ²⁺ waves, which were more common in YAC128 cortical neurons. Conversely, spontaneous axonal ER Ca ²⁺ release was associated with reduced AP-dependent axonal Ca ²⁺ events and consequent glutamate release. Together, our results suggest spontaneous release of axonal ER Ca ²⁺ stores oppositely regulates activity-dependent and -independent neurotransmitter release in HD, with potential implications for the fidelity and plasticity of cortical excitatory signaling.