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Featured ArticleResearch Articles, Systems/Circuits

Differential Subcellular Distribution and Release Dynamics of Cotransmitted Cholinergic and GABAergic Synaptic Inputs Modify Dopaminergic Neuronal Excitability

Keyrian Louis Le Gratiet, Christopher K. Anderson, Nagore Puente, Pedro Grandes, Charlotte Copas, Patrick C. Nahirney, Kerry R. Delaney and Raad Nashmi
Journal of Neuroscience 16 November 2022, 42 (46) 8670-8693; DOI: https://doi.org/10.1523/JNEUROSCI.2514-21.2022
Keyrian Louis Le Gratiet
1Department of Biology
2Division of Medical Sciences
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Christopher K. Anderson
1Department of Biology
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Nagore Puente
4Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country Universidad del Pais Vasco / Euskal Herriko Unibertsitatea, Leioa, Spain
5Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, E-48940, Leioa, Spain
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Pedro Grandes
4Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country Universidad del Pais Vasco / Euskal Herriko Unibertsitatea, Leioa, Spain
5Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, E-48940, Leioa, Spain
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Charlotte Copas
2Division of Medical Sciences
3Centre for Biomedical Research, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
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Patrick C. Nahirney
2Division of Medical Sciences
3Centre for Biomedical Research, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
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Kerry R. Delaney
1Department of Biology
3Centre for Biomedical Research, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
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Raad Nashmi
1Department of Biology
2Division of Medical Sciences
3Centre for Biomedical Research, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
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Abstract

We identified three types of monosynaptic cholinergic inputs spatially arranged onto medial substantia nigra dopaminergic neurons in male and female mice: cotransmitted acetylcholine (ACh)/GABA, GABA-only, and ACh only. There was a predominant GABA-only conductance along lateral dendrites and soma-centered ACh/GABA cotransmission. In response to repeated stimulation, the GABA conductance found on lateral dendrites decremented less than the proximally located GABA conductance, and was more effective at inhibiting action potentials. While soma-localized ACh/GABA cotransmission showed depression of the GABA component with repeated stimulation, ACh-mediated nicotinic responses were largely maintained. We investigated whether this differential change in inhibitory/excitatory inputs leads to altered neuronal excitability. We found that a depolarizing current or glutamate preceded by cotransmitted ACh/GABA was more effective in eliciting an action potential compared with current, glutamate, or ACh/GABA alone. This enhanced excitability was abolished with nicotinic receptor inhibitors, and modulated by T- and L-type calcium channels, thus establishing that activity of multiple classes of ion channels integrates to shape neuronal excitability.

SIGNIFICANCE STATEMENT Our laboratory has previously discovered a population of substantia nigra dopaminegic neurons (DA) that receive cotransmitted ACh and GABA. This study used subcellular optogenetic stimulation of cholinergic presynaptic terminals to map the functional ACh and GABA synaptic inputs across the somatodendritic extent of substantia nigra DA neurons. We determined spatially clustered GABA-only inputs on the lateral dendrites while cotransmitted ACh and GABA clustered close to the soma. We have shown that the action of GABA and ACh in cotransmission spatially clustered near the soma play a critical role in enhancing glutamate-mediated neuronal excitability through the activation of T- and L-type voltage-gated calcium channels.

  • cholinergic
  • GABA
  • nicotinic receptors
  • optogenetics
  • substantia nigra
  • synaptic transmission
  • cotransmission

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The Journal of Neuroscience: 42 (46)
Journal of Neuroscience
Vol. 42, Issue 46
16 Nov 2022
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Differential Subcellular Distribution and Release Dynamics of Cotransmitted Cholinergic and GABAergic Synaptic Inputs Modify Dopaminergic Neuronal Excitability
Keyrian Louis Le Gratiet, Christopher K. Anderson, Nagore Puente, Pedro Grandes, Charlotte Copas, Patrick C. Nahirney, Kerry R. Delaney, Raad Nashmi
Journal of Neuroscience 16 November 2022, 42 (46) 8670-8693; DOI: 10.1523/JNEUROSCI.2514-21.2022

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Differential Subcellular Distribution and Release Dynamics of Cotransmitted Cholinergic and GABAergic Synaptic Inputs Modify Dopaminergic Neuronal Excitability
Keyrian Louis Le Gratiet, Christopher K. Anderson, Nagore Puente, Pedro Grandes, Charlotte Copas, Patrick C. Nahirney, Kerry R. Delaney, Raad Nashmi
Journal of Neuroscience 16 November 2022, 42 (46) 8670-8693; DOI: 10.1523/JNEUROSCI.2514-21.2022
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Keywords

  • cholinergic
  • GABA
  • nicotinic receptors
  • optogenetics
  • substantia nigra
  • synaptic transmission
  • cotransmission

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