The striatum is a subcortical nucleus that regulates a number of complex activities ranging from voluntary action selection to the subconscious formation of habit. The coordination of these operations is mediated by the principle cells of the striatum, spiny projection neurons (SPNs). SPN activity is dictated by a confluence of cortical and thalamic glutamatergic inputs, their intrinsic excitability, and striatal microcircuits to achieve a desirable outcome. Striatal microcircuitry is of

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... lar interest as it has historically, been the most poorly described of these elements due to the inherent difficulty in studying a nucleus without a laminar organization. Consequently, our knowledge of the interneurons that compose these circuits is scant. The advent of transgenic mice and novel constructs allowing for the identification and selective excitation of these cells has provided the opportunity to attempt a comprehensive description of basic striatal physiology. Accordingly, the goal of this thesis work is to determine the function and regulation of one class of striatal interneuron known as the plateau and lowthreshold spiking interneurons (PLTSIs). We used a combination of optogenetics, pharmacology, and calcium imaging to test the hypothesis that these cells mediate a form of synaptic plasticity in SPNs. To investigate the regulation of PLTSIs we combined mapping studies using a monosynaptic Rabies virus (RV), optogenetics, and pharmacology. Glutamatergic inputs onto SPNs were found to undergo long term depression (LTD) when PLTSIs were optogenetically activated. One of many neuromodulators these cells synthesize is nitric oxide (NO). We found that this LTD was dependent on NO and occurred via a postsynaptic mechanism that relied on removal of AMPARs from postsynaptic synapses. LIST OF ABBREVIATIONS 2-AG -2-arachidonylglycerol 5-HT serotonin 5-HT2R -serotonin receptor 6-OHDA -6-hydroxydopamine, neurotoxin compound that selectively kills dopaminergic and noradrenergic neurons 8-Br-cGMP -8-Bromoguanosine 3'5'-cyclic monophosphate, cell permeable cGMP analog A2a -adenosine A2a receptor, selectively expressed by iSPNs, mainly in reference to A2a-Cre mice ACh -acetylcholine AChE -acetylcholinesterase ACSF -artificial cerebral spinal fluid AEA -anandamide AFDX-384 -M2/M4 selective antagonist AHP -afterhyperpolarization AM-251 -CB1R antagonist AMPARα-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (glutamate) BAC -bacterial artificial chromosome BAY 41-2272 -activator of sGC at an NO-independent regulatory site BK -big conductance Ca2+-activated K+ current Cav -voltage-gated Ca 2+ channel Cav1(1.2, 1.3) -L-type Ca 2+ channels Cav2/2 -N-type Ca 2+ channels CB1R, CB2R -cannabinoid 1 and 2 receptors (Gi/o-coupled) CgCx -cingulate cortex CGP 55845 -selective blocker of GABAB receptors ChAT -choline acetyltransferase ChI -cholinergic interneuron ChR2 -channelrhodopsin CM -centromedian thalamic nucleus CM/Pf -centromedian/parafascicular complex CR -calretinin, in reference to a subpopulation of calretinin expressing striatal interneurons DA -dopamine (DAR, dopamine receptor) D1R -dopamine 1 receptor (dSPN expression) D2R -dopamine 2 receptor (iSPN expression) DIC -differential interference contrast DHPG -selective agonist of group I metabotropic glutamate receptors. DYN -dynorphin, expressed by dSPNs eCB -endocannabinoids; 2-Arachidonoylglycerol and Anandamide eGFP -enhanced green fluorescent protein ENK -encephalin EPSC/P -excitatory post synaptic current/potential EP -entopeduncular nucleus (GPi, primates); projection site of dSPNs FSI -fast-spiking interneuron, express the parvalbumin Ca 2+ binding protein GABAγ-amino butyric acid GABAAR -ionotropic, ligand-gated receptor for GABA; considered inhibitory GABABR -metabotropic receptor for GABA Gabazine -selective blocker of GABAAR, synonymous with SR 95531 GC -guanylyl cyclase; may refer to soluble (sGC) or particulate (pGC); receptor of nitric oxide and atrial natriuretic peptides, respectively GIRK -G protein coupled inwardly-rectifying potassium channel GP -globus pallidus (GPe, primates); projection site of iSPNs GPe -external segment of the globus pallidus; projection site of iSPNs GPi -internal segment of the globus pallidus; projection site of dSPNs GPCR -G protein coupled receptor, class of metabotropic receptors HD -Huntington's disease IPSC/P -inhibitory post-synaptic current/potential L-DOPA -3,4-dihydroxy-L-phenylalanina, DA precursor used for symptomatic mgmt. of PD LID -Levodopa-induced dyskinesia L-NAME -NG-Nitro-L-arginine methyl ester hydrochloride, inhibitor of NO synthase LTD -long-term depression LTP -long-term potentiation mAChR -muscarinic acetylcholine receptor, metabotropic M1R -muscarine 1 receptor M4R -muscarine 4 receptor Mecamylamine hydrochloride -non-competitive nicotinic acetylcholine receptor antagonsit mGluR -metabotropic glutamate receptors MT-3 -muscarinic toxin 3, mamba toxin selective for M4 subtype of mAChRs MT-7 -muscarinic toxin 7, mamba toxin selective for M1 subtype of mAChRs NAc -nucleus accumbens; ventral striatum separated into the "core" and "shell" nAChR -nicotinic acetylcholine receptor; ionotropic receptors NADPH diaphorase -dihydronicotinamide adenine dinucleotide phosphate diaphorase; a marker for NOS (see below) NMDAR -N-methyl D-aspartate (NMDA) receptor (glutamate) nNOS -neuronal nitric oxide synthase NO -nitric oxide NO-LTD -nitric oxide induced long term depression nNOS -neuronal nitric oxide synthase, enzyme expressed in PLTSIs responsible for NO production NOS -nitric oxide synthase NPY -neuropeptide Y, peptide expressed by PLTSIs FIGURE 3.10.