Axonal Endoplasmic Reticulum Ca²⁺ Content Controls Release Probability in CNS Nerve Terminals

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• The endoplasmic reticulum (ER) is a ubiquitous organelle within neurons, extending throughout axons.
• Dysfunction of the axonal ER is linked to various neurological disorders.
• The specific role of ER calcium (Ca2+) dynamics at presynaptic nerve terminals remains largely unknown.

Purpose of the Study:

• To investigate the role of ER Ca2+ in presynaptic function.
• To develop and utilize novel tools for measuring axonal ER Ca2+.
• To understand how ER Ca2+ influences neurotransmitter release.

Main Methods:

• Development of genetically encoded, low-affinity, ER-targeted Ca2+ indicators.
• Optimization of these indicators for axonal ER Ca2+ measurements.
• Electrophysiological recordings and Ca2+ imaging in presynaptic terminals.

Main Results:

• Presynaptic function is critically dependent on ER Ca2+ content.
• Neuronal activity leads to net Ca2+ uptake into the presynaptic ER.
• Axonal ER Ca2+ regulates plasma membrane (PM) function by controlling STIM1 activation, impacting Ca2+ entry and release probability.

Conclusions:

• The presynaptic ER plays a vital role in regulating neurotransmitter release.
• ER Ca2+ dynamics are a key determinant of presynaptic function.
• These findings provide a foundation for understanding ER-related neurological diseases.