title: Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons.
abstract: Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
authors.forename: Jae-Ick
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
authors.forename: Subhashree
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA. Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Sarah X
authors.initials: SX
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA. Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA. Pathology Service 113B, San Francisco VA Medical Center, San Francisco, CA 94121, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94304, USA. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94304, USA. dingjun@stanford.edu.
authors.forename: Jun B
authors.initials: JB
authors.lastname: Ding
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D063425:Binge Drinking / Q000097:blood / Q000201:enzymology / Q000235:genetics; D059290:Dopaminergic Neurons / Q000201:enzymology / Q000378:metabolism*; D000431:Ethanol / Q000097:blood / Q000494:pharmacology; D019143:Evolution, Molecular; D005260:Female; D055785:Gene Knockdown Techniques; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D051379:Mice; D050697:Retinal Dehydrogenase; D012201:Reward; D017384:Sequence Deletion; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis*
chemical_list: D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase