The role of non-canonical GABA synthesis in midbrain dopamine neurons on striatal inhibition

Dopamine (DA) producing neurons regulate motor movement, executive behavior and addiction, and dysregulation of DA neurons contribute to several well-known diseases including attention deficit disorder and Parkinson’s disease. Midbrain DA neurons deliver DA to the striatum, a large structure that is at the crux of motor and reward pathways. Recent studies from our lab and others have found that DA neurons possess the ability to co-release multiple chemicals to the striatum. We have found that GABA, the most prevalent inhibitory chemical transmitter in the nervous system, is also co-packaged and co-released by DA neurons. GABA co-packaged with DA is difficult to study; therefore, the function and source of GABA produced in DA neurons remain unknown. Due to the critical role that DA neurons play in pathophysiology, it is important to examine the function of its co-released GABA.

This grant aims to study GABA biosynthesis in midbrain DA neurons and it’s effect on striatal inhibition. Our pilot studies suggest a novel, alternative pathway for GABA synthesis: we have found a strong link between the enzyme aldehyde dehydrogenase (ALDH1a1) and GABA production in DA neurons. Coincidentally, mutations of ALDH1a1 are linked to the incidence of alcoholism in human populations. While this ALDH1a1-dependent pathway is common in plants and in fish, we provide the first report of its presence in mammals, thus providing a broader reach and impact for our findings. Furthermore, the intriguing relationship between GABA produced in DA neurons and alcoholism advocates the need to examine this ALDH1a1-dependent GABA synthesis pathway.  

Successful completion of the proposed research will provide important answers to questions that remain on GABA biosynthesis and the unique function of these transmitters in the striatum. Using advanced mouse genetics, virus construction, electrical recordings and imaging, our research will also further the examination of the sites at which chemical co-release is present. The unique, multi-faceted approach proposed in this grant will finally allow us to advance these important questions, and the missing information we uncover will be essential for our comprehensive understanding of the synaptic mechanisms utilized by midbrain DA neurons. Together, we hope that the results of this research will provide earlier targets for neuropsychiatric diseases.