title: Are striatal tyrosine hydroxylase interneurons dopaminergic?
abstract: Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH-Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)-TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP-TH interneurons. Optogenetic activation of striatal EGFP-TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons.
authors.affiliation: Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102.
authors.forename: Harry S
authors.identifier: http://orcid.org/0000-0002-9502-0973
authors.initials: HS
authors.lastname: Xenias
authors.affiliation: Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Ibáñez-Sandoval
authors.affiliation: Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102.
authors.forename: Tibor
authors.initials: T
authors.lastname: Koós
authors.affiliation: Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102 jtepper@andromeda.rutgers.edu.
authors.forename: James M
authors.identifier: http://orcid.org/0000-0002-8643-4082
authors.initials: JM
authors.lastname: Tepper
mesh_terms: D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004558:Electric Stimulation; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism* / Q000502:physiology; D007395:Interneurons / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology; D062308:Optogenetics; D010775:Photic Stimulation; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine
keywords: GABA; dopamine; interneuron; neostriatum; optogenetics; voltammetry