Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M4 Muscarinic Receptor

Mark S Moehle; Tristano Pancani; Nellie Byun; Samantha E Yohn; George H Wilson 3rd; Johnathan W Dickerson; Daniel H Remke; Zixiu Xiang; Colleen M Niswender; Jürgen Wess; Carrie K Jones; Craig W Lindsley; Jerri M Rook; P Jeffrey Conn

doi:10.1016/j.neuron.2017.12.008

Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M₄ Muscarinic Receptor

Neuron. 2017 Dec 20;96(6):1358-1372.e4. doi: 10.1016/j.neuron.2017.12.008.

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
² Vanderbilt Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, TN, USA; Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN, USA.
³ Vanderbilt Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, TN, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁴ Molecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, MD, USA.
⁵ Vanderbilt Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, TN, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: jeff.conn@vanderbilt.edu.

Abstract

Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M₄) to oppose cAMP-dependent dopamine receptor subtype 1 (D₁) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons. This induces a tonic inhibition of transmission at direct pathway synapses and D₁-mediated activation of motor activity. These studies provide important new insights into the unique role of M₄ in regulating BG function and challenge the prevailing hypothesis of the centrality of striatal ChIs in opposing dopamine regulation of BG output.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholine / metabolism
Animals
Basal Ganglia / cytology*
Basal Ganglia / diagnostic imaging
Basal Ganglia / physiology
Channelrhodopsins / genetics
Channelrhodopsins / metabolism
Choline O-Acetyltransferase / metabolism
Cholinergic Agents / pharmacology
Cholinergic Neurons / drug effects
Cholinergic Neurons / physiology*
Dopamine / metabolism*
Dopamine / pharmacology
Inhibitory Postsynaptic Potentials / drug effects
Inhibitory Postsynaptic Potentials / genetics
Locomotion / drug effects
Locomotion / genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurotransmitter Agents / pharmacology
Oxygen / blood
Pars Reticulata / cytology
Pars Reticulata / diagnostic imaging
Pars Reticulata / physiology*
Pedunculopontine Tegmental Nucleus / cytology
Receptor, Muscarinic M4 / genetics
Receptor, Muscarinic M4 / metabolism*
Receptors, Dopamine D1 / genetics
Receptors, Dopamine D1 / metabolism
Signal Transduction / drug effects
Signal Transduction / physiology

Substances

Channelrhodopsins
Cholinergic Agents
Neurotransmitter Agents
Receptor, Muscarinic M4
Receptors, Dopamine D1
Choline O-Acetyltransferase
Acetylcholine
Oxygen
Dopamine