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Science. 2015 Oct 2;350(6256):102-6. doi: 10.1126/science.aac4690.

Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons.

Author information

1
Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
2
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.
3
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.
4
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.

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.

PMID:
26430123
PMCID:
PMC4725325
DOI:
10.1126/science.aac4690
[Indexed for MEDLINE]
Free PMC Article

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