Neostriatal GABAergic Interneurons Mediate Cholinergic Inhibition of Spiny Projection Neurons.
Synchronous optogenetic activation of striatal cholinergic interneurons ex vivo produces a disynaptic inhibition of spiny projection neurons composed of biophysically distinct GABAAfast and GABAAslow components. This has been shown to be due, at least in part, to activation of nicotinic receptors on GABAergic NPY-neurogliaform interneurons that monosynaptically inhibit striatal spiny projection neurons. Recently, it has been proposed that a significant proportion of this inhibition is actually mediated by activation of presynaptic nicotinic receptors on nigrostriatal terminals that evoke GABA release from the terminals of the dopaminergic nigrostriatal pathway. To disambiguate these the two mechanisms, we crossed mice in which channelrhodopsin is endogenously expressed in cholinergic neurons with Htr3a-Cre mice, in which Cre is selectively targeted to several populations of striatal GABAergic interneurons, including the striatal NPY-neurogliaform interneuron. Htr3a-Cre mice were then virally transduced to express halorhodopsin to allow activation of channelrhodopsin and halorhodopsin, individually or simultaneously. Thus we were able to optogenetically disconnect the interneuron-spiny projection neuron (SPN) cell circuit on a trial-by-trial basis. As expected, optogenetic activation of cholinergic interneurons produced inhibitory currents in SPNs. During simultaneous inhibition of GABAergic interneurons with halorhodopsin, we observed a large, sometimes near complete reduction in both fast and slow components of the cholinergic-evoked inhibition, and a delay in IPSC latency. This demonstrates that the majority of cholinergic-evoked striatal GABAergic inhibition is derived from GABAergic interneurons. These results also reinforce the notion that a semiautonomous circuit of striatal GABAergic interneurons is responsible for transmitting behaviorally relevant cholinergic signals to spiny projection neurons.



The circuitry between neurons of the striatum has been recently described to be far more complex than originally imagined. One example of this phenomenon is that striatal cholinergic interneurons have been shown to provide intrinsic nicotinic excitation of local GABAergic interneurons, which then inhibit the projection neurons of the striatum. As deficits of cholinergic interneurons are reported in patients with Tourette syndrome, the normal functions of these interneurons are of great interest. Whether this novel route of nicotinic input constitutes a major output of cholinergic interneurons remains unknown. The study addressed this question using excitatory and inhibitory optogenetic technology, so that cholinergic interneurons could be selectively activated and GABAergic interneurons selectively inhibited to determine the causal relationship in this circuit.
Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 17102.
Thomas W
0000-0002-3170-8365
TW
Faust
Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 17102.
Maxime
0000-0001-6039-816X
M
Assous
Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 17102.
James M
0000-0002-8643-4082
JM
Tepper
Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 17102 tibkoos@andromeda.rutgers.edu.
Tibor
T
Koós
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D000075402:Channelrhodopsins; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D018678:Cholinergic Agents / Q000494:pharmacology; D059329:Cholinergic Neurons / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009478:Neuropeptide Y / Q000378:metabolism; D018408:Patch-Clamp Techniques; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; D000075402:Channelrhodopsins; D018678:Cholinergic Agents; D004268:DNA-Binding Proteins; C511230:Htr3a protein, mouse; D008164:Luminescent Proteins; D009478:Neuropeptide Y; D044406:Receptors, Serotonin, 5-HT3; D014157:Transcription Factors; C088395:VEZF1 protein, human; C054562:yellow fluorescent protein, Bacteria; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase
GABA-Aslow; cholinergic interneuron; neurogliaform; optogenetics; striatum