Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake

Cell Rep. 2022 Apr 19;39(3):110716. doi: 10.1016/j.celrep.2022.110716.


Dopamine (DA)-releasing neurons in the substantia nigra pars compacta (SNcDA) inhibit target cells in the striatum through postsynaptic activation of γ-aminobutyric acid (GABA) receptors. However, the molecular mechanisms responsible for GABAergic signaling remain unclear, as SNcDA neurons lack enzymes typically required to produce GABA or package it into synaptic vesicles. Here, we show that aldehyde dehydrogenase 1a1 (Aldh1a1), an enzyme proposed to function as a GABA synthetic enzyme in SNcDA neurons, does not produce GABA for synaptic transmission. Instead, we demonstrate that SNcDA axons obtain GABA exclusively through presynaptic uptake using the membrane GABA transporter Gat1 (encoded by Slc6a1). GABA is then packaged for vesicular release using the vesicular monoamine transporter Vmat2. Our data therefore show that presynaptic transmitter recycling can substitute for de novo GABA synthesis and that Vmat2 contributes to vesicular GABA transport, expanding the range of molecular mechanisms available to neurons to support inhibitory synaptic communication.

Keywords: Aldh1a1; CP; GABA; Gat1; Neuroscience; SLC18A2; Slc6a1; VMAT2; basal ganglia; dopamine; striatum; synaptic transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Corpus Striatum
  • Dopamine*
  • Dopaminergic Neurons*
  • Mesencephalon
  • Substantia Nigra / physiology
  • gamma-Aminobutyric Acid


  • gamma-Aminobutyric Acid
  • Dopamine