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

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Science  02 Oct 2015:
Vol. 350, Issue 6256, pp. 102-106
DOI: 10.1126/science.aac4690

An alternative way of making GABA

Midbrain dopaminergic neurons release both the inhibitory neurotransmitter GABA and dopamine. In the central nervous system, GABA synthesis is usually mediated by two glutamate decarboxylases (GAD65 and GAD67). Kim et al. found that midbrain dopaminergic neurons use a different, evolutionary conserved GABA synthesis pathway that is independent of GAD65 and GAD67. These cells synthesize GABA from putrescine via the enzymes diamine oxidase and aldehyde dehydrogenase 1a1. GABA synthesized by this pathway accounts for approximately 70% of co-released GABA.

Science, this issue p. 102


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.

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