Cholinergic Modulation of GABAergic Inhibition Dynamics In The Striatum
The striatum contains medium spiny neurons (MSNs) classified by their axonal projection and expression of dopamine receptors into D1+ and D2+ MSNs; and interneurons including choline acetyltransferase expressing interneurons (ChAT+) that influence MSN activity by triggering GABA release. Here, I identify the potentialsource of this GABA. In addition, I characterize GABAA receptors that mediate the GABA response produced by distinct classes of neurons.By studying nAChR mediated response in MSNs and in GABAergic interneurons classified as neuropeptide Y (NPY+), parvalbumin (PV+) and tyrosine hydroxylase (TH+), I show direct nAChR mediated response in interneurons but not MSNs, where the response is indirect and mediated through GABAA receptors. To identify the neurons that mediate this GABA response, I performed dual recordings from GABAergic interneurons and MSNs. TH+, PV+, and NPY+ NGF interneurons all form synapses on MSNs, but only TH+ and NPY+ NGF interneurons contribute to nAChR mediated GABAergic responses in MSNs.Through different firing patterns that produce transient and sustained GABA conductance in MSNs, GABAergic interneurons adapt distinct physiological roles. By performing single and dual recordings, I report distinct GABA responses produced by PV+ and NPY+ NGF interneurons. In MSNs, phasic current is mediated by synaptic GABAA receptors containing α2, β2 and a γ subunit; whereas tonic GABA current is mediated by extrasynaptic receptors containing α4, δ (adult mice), and α5 (young mice) subunit. Using β3 and δ subunit selective drugs in mice that lack either subunit, I found that the β3 subunit is not a component of δ-containing extrasynaptic receptor pool, but is involved in mediating spontaneous slow IPSCs from NGF interneurons.To further characterize GABAA receptors, I found that optogenetic activation of D2+, TH+, and PV+ neurons produced a GABA response that exhibited different sensitivity to GABA drugs, demonstrating the expression of various GABAA receptor subtypes in MSNs. Specifically, D2+ stimulation activated β3 and γ2-containing; TH+ stimulation activated β3-containing; and PV+ stimulation activated α1, β3, and γ2-containing receptors. Taken together, my findings contribute to the understanding of striatal neurons and microcircuitry and set the stage for future studies that will continue to contribute to our understanding of the striatum.
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Itten, Johannes; 1888 - 1967 (1964)
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