Regulation of presynaptic neurotransmission by macroautophagy

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• The mechanistic target of rapamycin (mTOR) pathway regulates crucial cellular processes including growth, survival, and autophagy.
• Macroautophagy, a key cellular degradation process, is regulated by mTOR inactivation and is vital for synaptic plasticity.
• The role of macroautophagy in presynaptic function remains largely unexplored.

Purpose of the Study:

• To investigate whether macroautophagy modulates presynaptic function in dopaminergic neurons.
• To elucidate the impact of mTOR inhibition on presynaptic structure and neurotransmission.

Main Methods:

• Utilized the mTOR inhibitor rapamycin to induce macroautophagy in dopaminergic axons.
• Examined changes in axonal morphology, synaptic vesicle numbers, and dopamine release.
• Employed transgenic mice with macroautophagy deficiency specifically in dopaminergic neurons for comparative analysis.

Main Results:

• Rapamycin treatment led to increased autophagic vacuoles in presynaptic dopaminergic axons.
• This was accompanied by reduced axonal volume, fewer synaptic vesicles, and diminished evoked dopamine release.
• Mice with selective dopaminergic macroautophagy deficiency showed enhanced dopamine secretion and accelerated recovery, with rapamycin having no effect on dopamine release.

Conclusions:

• Macroautophagy, following mTOR inhibition in presynaptic terminals, rapidly impacts presynaptic structure.
• This process significantly alters neurotransmission by modulating synaptic vesicle dynamics and dopamine release.
• Macroautophagy plays a critical role in maintaining normal presynaptic function and dopamine signaling.