Defining glycine receptor control of striatal cholinergic interneuron function in health and in disease

Neurotransmitters in a brain region called the striatum are vitally important for supporting our normal everyday actions and motivations. An imbalance in neurotransmission by acetylcholine and dopamine in multiple neurological and neuropsychiatric disorders leads to problems such as poor movement control as seen in Parkinson’s disease, and the compulsive behaviours seen in addiction disorders. These disorders present significant burdens on human health and society, with dementias and substance use disorders contributing leading causes of mortality and morbidity worldwide. The brain mechanisms that regulate acetylcholine and dopamine function in the striatum remain incompletely defined. While dopamine has been the subject of scrutiny for several decades, acetylcholine has received comparatively less attention and yet offers a potentially untapped seam for rescuing striatal function in disease. If we could better understand the mechanisms that govern how acetylcholine neurons in the striatum are controlled, we might identify new options for treating dysfunction in disease. Newly emerging evidence suggests that the activity of acetylcholine-producing neurons in the striatum are modulated by diverse neuromodulators and their receptors. This insight comes at a time when we are undergoing a paradigm shift in understanding the neuromodulation in the brain by the molecule glycine. Glycine has been long known to act at a specific receptor that rapidly inhibits brain cell activity, but very recently, new discoveries have uncovered two additional types of glycine receptors that either rapidly or slowly excite brain cells. Surprisingly, our unpublished data reveal that within the striatum, acetylcholine-producing neurons are unique in expressing all three types of glycine receptors, suggesting a previously unknown but important role for glycine in shaping acetylcholine function. These new discoveries suggest in turn that glycine receptors might offer a novel means to modulate striatal acetylcholine function in disease. In this project, we will examine for the first time, the fundamentally important question of whether the three different types of glycine receptors modulate acetylcholine function in health and disease. We have obtained some preliminary data that strongly suggest important roles. In health, we will establish whether each glycine receptor type impacts on acetylcholine neuron activity and acetylcholine release, and on striatally-regulated behaviours. We will use state-of-the art methodology to allow us to manipulate each receptor on acetylcholine neurons and to sense subsecond acetylcholine signals to understand impact on acetylcholine function. We will also try and identify a potential cellular source of the striatal glycine that normally acts at these receptors. In Parkinson's disease, we will address whether there are changes to glycine receptor control of acetylcholine signalling. We will look for these receptors in mouse models of Parkinson's disease and in human patient brains, and test the hypothesis that targeting key glycine receptors can acetylcholine signalling in mouse models. Overall, we expect this timely original project to greatly increase fundamental knowledge about how newly discovered glycine receptors control brain function in health and disease. We expect to find that striatal acetylcholine neurons orchestrate a response to glycine through multiple types of receptors, to govern acetylcholine release and function, and that there will be disruptions to how glycine receptors control acetylcholine function in Parkinson's disease. This work could also open up potential new avenues for drug discovery, by identifying disruptions to glycine receptor biology that could be targets for future treatments for Parkinson's disease and other striatal disorders.