Cell type-specific roles of PLCγ1 in the regulation of synaptic structure and function

Abstract

Neurotransmitters like dopamine and GABA play crucial roles in cognitive and motor functions in the central nervous system (CNS). Dopamine, a monoamine neurotransmitter, is vital for voluntary movement, reward-related learning, emotion, and motivation. GABA, on the other hand, is an inhibitory neurotransmitter that maintains the excitation-inhibition balance in the brain. Myelination, facilitated by oligodendrocytes, is essential for efficient neural signaling. Disturbances in these processes can lead to neurological and psychiatric disorders, making it imperative to understand the underlying molecular mechanisms. This dissertation explores the multifaceted role of phospholipase Cγ1 (PLCγ1) in various neurological functions and disorders. I provide a comprehensive analysis of PLCγ1's involvement in dopamine and GABAergic neurons and its impact on myelination processes mediated by neural stem cell-derived oligodendrocytes. Current understanding of these neurological functions and disorders is limited, particularly concerning the intracellular signaling pathways. PLCγ1, an enzyme activated by receptor tyrosine kinases, is implicated in these pathways but its specific role remains unclear. This research addresses this gap by investigating the role of PLCγ1 in dopamine and GABAergic neurons and oligodendrocyte function. In Chapter 3, I demonstrate that PLCγ1 does not affect the development of dopamine neurons but plays a crucial role in dopamine release. This finding was supported by experiments using dopamine neuron-specific PLCγ1 conditional knockout mice, which revealed unexpected facilitation of dopamine release upon PLCγ1 disruption and alteration of synaptic vesicle regulatory proteins. In Chapter 4, I suggest that PLCγ1 is essential for maintaining inhibitory synaptic transmission. GABAergic neuron-specific PLCγ1 knockout mice exhibited seizures and behavioral alterations, highlighting the importance of PLCγ1 in regulating GABAergic function in aged mice. In Chapter 5, my research extends to the role of PLCγ1 in myelination. Using neural stem cell-specific PLCγ1 knockout mice, I found that PLCγ1 is a crucial regulator in the remyelination process, with its inhibition impairing the differentiation of NSCs into oligodendrocytes. Finally, in Chapter 6, I summarize the main findings of this dissertation and propose future work. The findings of this study open avenues for further research on PLCγ1 as a potential therapeutic target in various neurological disorders. Understanding the role of PLCγ1 in dopamine and GABAergic neurons and in myelination could lead to new strategies for treating conditions such as Parkinson's disease, epilepsy, and multiple sclerosis. In addition, this research contributes to the broader field of neuroscience by providing insights into the complex intracellular mechanisms that underpin critical neurological functions and disorders.