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Striatal cholinergic neurotransmission requires VGLUT3
Alexandra B Nelson1, Timothy G Bussert2, Anatol C Kreitzer3
1Gladstone Institute for Neurological Disease, J. David Gladstone Institutes, San Francisco, California 94158, Department of Neurology, University of California, San Francisco 94117.
Summary
Vesicular glutamate transporter 3 (VGLUT3) enables neurotransmitter corelease from cholinergic interneurons, impacting striatal fast-spiking interneurons and medium spiny neurons. Its absence disrupts signaling, highlighting VGLUT3
Area of Science:
- Neuroscience
- Neurochemistry
Background:
- Many neurons co-release multiple neurotransmitters, but the function of this corelease remains largely unknown.
- Striatal cholinergic interneurons are known to release both glutamate and acetylcholine (ACh).
- Glutamate vesicular loading enhances ACh content in these neurons.
Purpose of the Study:
- To investigate the physiological role of glutamate and acetylcholine corelease from striatal cholinergic interneurons.
- To determine the dependence of these coreleased neurotransmitters on vesicular glutamate transporter 3 (VGLUT3).
- To elucidate the impact of VGLUT3 on striatal network function, particularly on fast-spiking interneurons (FSIs) and medium spiny neurons (MSNs).
Main Methods:
- Optogenetics and whole-cell recordings in mice.
- Electrophysiological analysis of synaptic currents.
- Investigation of VGLUT3 expression and function.
Main Results:
- Optogenetic stimulation of cholinergic interneurons evoked monosynaptic glutamate- and ACh-mediated currents in FSIs, dependent on VGLUT3.
- Glutamate released by cholinergic interneurons activated both AMPA and NMDA receptors on FSIs.
- Loss of VGLUT3 reduced glutamatergic and cholinergic inputs to FSIs and decreased disynaptic GABAergic inhibition of MSNs.
Conclusions:
- VGLUT3 is essential for normal cholinergic signaling onto FSIs.
- VGLUT3 supports acetylcholine-dependent disynaptic inhibition of MSNs.
- VGLUT3 plays a critical role in modulating striatal network activity through its influence on glutamatergic and cholinergic transmission.
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