Abstract
Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.DOI: http://dx.doi.org/10.7554/eLife.01936.001.
Highlights
Dopamine (DA)-releasing neurons in the mammalian midbrain play an important role in fundamental behaviors, including motivation, reinforcement learning and motor control, and their dysfunction is associated with a wide range of neuropsychiatric disorders (Wise, 2004; Costa, 2007; Schultz, 2007; Morris et al, 2009; Redgrave et al, 2010)
Our results provide strong evidence that the inhibitory transmitter released by midbrain DA neurons is gamma-aminobutyric acid (GABA), and suggest that GABA co-release is a general feature of all midbrain DA neurons
We recently reported that activation of substantia nigra pars compacta (SNc) axons in dorsal striatum evokes monosynaptic, GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in striatal projection neurons (SPNs)
Summary
Dopamine (DA)-releasing neurons in the mammalian midbrain play an important role in fundamental behaviors, including motivation, reinforcement learning and motor control, and their dysfunction is associated with a wide range of neuropsychiatric disorders (Wise, 2004; Costa, 2007; Schultz, 2007; Morris et al, 2009; Redgrave et al, 2010). Each pathway arises from distinct groups of GABAergic striatal projection neurons (SPNs) that differ, amongst other things, in their response to DA (Gerfen and Surmeier, 2011; Tritsch and Sabatini, 2012). By providing DA to the striatum, SNc and VTA neurons are believed to play a pivotal role in balancing the activity of direct- and indirect-pathway SPNs. our understanding of the cellular and molecular mechanisms employed by DA neurons to modulate striatal function remains incomplete
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