The GABAaergic nature of dopamine synapses and its functional role in the brain

Abstract

Dopamine is one of the most important neurotransmitters in our brain. It is known to regulate essential brain functions such as voluntary movement, action selection, and reward-related behaviors. Malfunction of the dopamine system can lead to various brain disorders such as Parkinson’s disease, attention deficit hyperactivity disorder (ADHD), schizophrenia, etc. Diffuse modulatory neurotransmitters including dopamine, serotonin, and norepinephrine are transmitted through the diffusion of the neurotransmitters. Therefore, they are considered to be slow and non-synapse-specific. However, recent studies show that fast neurotransmitters, namely γ-aminobutyric acid (GABA) or glutamate, are co-transmitted with dopamine. Furthermore, NL2 (neuroligin-2), which is known to be an inhibitory postsynaptic cell adhesion molecule, has recently been discovered to be in close proximity to dopamine boutons. This spatial restriction of synaptic effects via the co-transmission of fast-acting neurotransmitters suggests that the physiological actions of dopamine synapses might be more synapse- specific. Although the roles of the neurotransmitter dopamine and dopamine neurons have been intensively studied, the precise molecular structure and physiological function of dopaminergic synapses remain unclear in various regions of the brain. In this dissertation, I define and characterize the dopamine synapses that co-transmit GABA. Furthermore, the possible role of the co-transmitted GABA in the dopamine synapse and various animal behaviors such as willed movement and reward learning is revealed. In Chapter 3, I show that dopamine transmission is strongly correlated with GABA co- transmission across the brain. Regardless of the amount of dopamine transmission in the brain region, a strong correlation was found between dopamine and GABA co-transmission. However, there were no pronounced correlations between dopamine and glutamate co-transmission. Furthermore, I newly suggest the concept of ‘GABAergic-like dopamine synapses’. These are dopamine synapses that can co-transmit GABA and form connections between dopaminergic presynaptic boutons and GABAergic postsynaptic sites. These GABAergic-like dopamine synapses have marked regional heterogeneity in their distribution and spatial patterns across brain regions. I found that GABAergic-like dopamine synapses and conventional GABAergic synapses show different clustering patterns in the dendrite of postsynaptic spiny projection neurons and various physiological differences. Moreover, I suggest the possible molecular mechanisms behind the physiological differences between these two synapses. Interestingly, I found that GABAergic synaptic contact and transmission might be critical for the maintenance and survival of dopamine synapses. In addition, my research shows that GABA transmission precedes alterations in DA transmission and synapse structure in several animal models of Parkinson’s disease. In Chapter 4, I visualize the dopamine and GABA co-transmission signals utilizing recently developed dopamine and GABA sensors. I also developed a new imaging paradigm that can detect dopamine and GABA at the same time. Based on this in vitro data, I suggested an in vivo fiber photometry experimental scheme that would be possible to detect dopamine and GABA from various brain regions in sync with their behavior. Finally, in Chapter 5, I summarize the major findings of this dissertation and discuss future work. Altogether, my research explores the characteristics and functions of GABAergic-like dopamine synapses in the healthy and diseased brain. My current and future research on the possible functions of GABA co-transmission at dopamine synapses will open numerous doors to a better understanding of synaptic actions in dopamine synapses in the brain. In addition, some of the main findings of my research can help find new insights into the clinical approach for the diagnosis and treatment of dopamine-related neurodegenerative diseases.