Nicotinic receptor subtype-selective circuit patterns in the subthalamic nucleus.
The glutamatergic subthalamic nucleus (STN) exerts control over motor output through nuclei of the basal ganglia. High-frequency electrical stimuli in the STN effectively alleviate motor symptoms in movement disorders, and cholinergic stimulation boosts this effect. To gain knowledge about the mechanisms of cholinergic modulation in the STN, we studied cellular and circuit aspects of nicotinic acetylcholine receptors (nAChRs) in mouse STN. We discovered two largely divergent microcircuits in the STN; these are regulated in part by either α4β2 or α7 nAChRs. STN neurons containing α4β2 nAChRs (α4β2 neurons) received more glutamatergic inputs, and preferentially innervated GABAergic neurons in the substantia nigra pars reticulata. In contrast, STN neurons containing α7 nAChRs (α7 neurons) received more GABAergic inputs, and preferentially innervated dopaminergic neurons in the substantia nigra pars compacta. Interestingly, local electrical stimuli excited a majority (79%) of α4β2 neurons but exerted strong inhibition in 58% of α7 neurons, indicating an additional diversity of STN neurons: responses to electrical stimulation. Chronic exposure to nicotine selectively affects α4β2 nAChRs in STN: this treatment increased the number of α4β2 neurons, upregulated α4-containing nAChR number and sensitivity, and enhanced the basal firing rate of α4β2 neurons both ex vivo and in vivo. Thus, chronic nicotine enhances the function of the microcircuit involving α4β2 nAChRs. This indicates chronic exposure to nicotinic agonist as a potential pharmacological intervention to alter selectively the balance between these two microcircuits, and may provide a means to inhibit substantia nigra dopaminergic neurons.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, and.
Cheng
http://orcid.org/0000-0001-9649-7450
C
Xiao
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, and Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015.
Julie M
JM
Miwa
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, and.
Brandon J
http://orcid.org/0000-0003-0381-028X
BJ
Henderson
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, and.
Ying
Y
Wang
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, and.
Purnima
P
Deshpande
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, and.
Sheri L
SL
McKinney
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, and lester@caltech.edu.
Henry A
http://orcid.org/0000-0002-5470-5255
HA
Lester
D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects*; D020531:Subthalamic Nucleus / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects
D018678:Cholinergic Agents; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D018698:Glutamic Acid; D009538:Nicotine
Parkinson's disease; alpha4beta2; alpha7; chronic nicotine; substantia nigra; upregulation