9 October 2012. A study published online October 3 in Nature provides a novel function for midbrain dopamine neurons: inhibiting their targets through GABA release. Bernardo Sabatini and his team at Boston’s Harvard University used mouse optogenetics to demonstrate that the activation of substantia nigra pars compacta (SNc) dopamine neurons inhibits the firing of striatal projection neurons through release of GABA. Surprisingly, this GABA release is independent of the vesicular GABA transporter (VGAT), but depends on the vesicular monoamine transporter VMAT2.
Although a myriad of neurotransmitters are implicated in schizophrenia, dopamine has been schizophrenia’s first and most enduring culprit. The dopamine hypothesis was originally formulated over 40 years ago (see SRF Hypothesis by Anissa Abi-Dargham), and even today, dysfunctional dopamine neurons remain key players in the positive and negative symptoms of the illness (Howes and Kapur, 2009).
A hyperactive subcortical dopamine system is thought to underlie the psychosis of schizophrenia. Prominent members of the dopamine system within the midbrain include the SNc and ventral tegmental area, regions that are home to the two largest populations of dopamine neurons. These midbrain neurons both project to the striatum and, through dopamine release, activate direct-pathway striatal projection neurons (SPNs) and inhibit indirect-pathway SPNs (Gerfen and Surmeier, 2011). Altered activation of the midbrain has been observed in schizophrenia, and correlates with delusional symptoms (see SRF related news story), and neurochemical imaging studies have reported increases in striatal dopamine synthesis capacity, availability, and release (Howes and Kapur, 2009). However, midbrain dopamine neurons also express neuropeptides, and some release glutamate, suggesting that the activity of these cells may extend beyond dopamine (Chuhma et al., 2004).
Lighting up the midbrain
In the current study, first author Nicolas Tritsch and colleagues expressed the light-activated channelrhodopsin-2 cation channel in SNc dopamine neurons so that blue light could be used to turn on these cells (see SRF related news story). Activation of midbrain dopamine neurons resulted in a hyperpolarization of SPNs that was abolished by a GABAA receptor antagonist, suggesting an involvement of these receptors in the inhibitory response of the dopamine neurons. The researchers next addressed whether the GABAA receptor activation occurred through the recruitment of GABA neurons or more directly through GABA release in the dopamine neurons themselves, finding evidence in support of the latter hypothesis.
Surprisingly, GABA release from dopamine neurons appears to be independent of VGAT, the only known mechanism for loading GABA into synaptic vesicles that is considered to be essential for inhibitory neurotransmission (Wojcik et al., 2006). Elimination of VGAT from dopamine neurons did not alter light-evoked inhibitory current. In addition, deletion of the vesicular glutamate transporter VGLUT2, which loads the GABA precursor glutamate into vesicles, also produced no effect on the light-evoked inhibitory current, ruling out the possibility that GABA synthesis occurs inside vesicles. Interestingly, inhibitory current was eliminated in slices treated with VMAT2 antagonists, suggesting that VMAT2 is required for GABA release from midbrain dopamine neurons. Although VMAT2 is known to transport many neurotransmitters, including dopamine, the current study is the first report of a GABA transporter function.
Taken together, the data from this study suggest a new inhibitory role of dopamine neurons on SPNs that is dependent on VMAT2-mediated packaging of GABA into synaptic vesicles. However, as noted by the authors, the possibility that another neurotransmitter besides GABA acts on GABAA receptors to mediate this effect cannot be excluded. And the fact that VMAT2 is expressed in all monoaminergic neurons suggests that GABA release may extend to other types of neurons. In fact, GABA release from dopamine neurons has been reported in the retina and olfactory bulb (Hirasawa et al., 2009; Maher and Westbrook, 2008). These findings also raise the question of whether the altered GABA synthesis observed in the cortical interneurons of schizophrenia subjects (see SRF related news story) may extend to subcortical dopamine neurons.—Allison A. Curley.
Tritsch NX, Ding JB, Sabatini BL. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature. 2012 Oct 3. Abstract