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

Dopamine (DA)-releasing neurons in the substantia nigra pars compacta (SNc(DA)) inhibit target cells in the striatum through postsynaptic activation of gamma-aminobutyric acid (GABA) receptors. However, the molecular mechanisms responsible for GABAergic signaling remain unclear, as SNc(DA) 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 SNc(DA) neurons, does not produce GABA for synaptic transmission. Instead, we demonstrate that SNc(DA) 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.

Automated summary

This study reveals that GABA synthesis in SNc(DA) neurons is not mediated by Aldh1a1 enzyme, but is obtained through presynaptic uptake by Gat1 protein and then packaged into synaptic vesicles for release by Vmat2 protein. This finding expands the range of molecular mechanisms available to neurons to support inhibitory synaptic communication.