In this project, we want to obtain a mechanistic understanding of how nAChRs expressed by striatal cholinergic interneurons (CINs) control the function of these neurons and how this control changes the activity of striatal circuits and ultimately the animals’ behavior.
Striatum is a peculiar structure in many aspects, including nicotinic expression. While there is a high level of nAChR expression in the striatum, the vast majority of the receptors are present in axon terminals projecting to the striatum from other brain regions. Most striatal neurons themselves do not express nAChRs at all, however, it is known that nAChRs can be expressed by specific types of striatal interneurons that represent less than 5 % of striatal neurons.
The scarcity and specificity of nAChRs in the striatum are curious for several reasons. Possibly the most obvious one is the functional significance of the small population of nAChRs expressed by specific types of striatal neurons. Given their small numbers, do these receptors matter at all and how can they tune striatal circuits and the associated behavior?
We have already answered some of these questions in our Abbondanza et al., 2022 publication but as it is commonly the case, the few answers led us to even more questions. We found that the vast majority of heteromeric beta2-containing nAChRs (beta2* nAChRs, the most common type of nAChRs in the striatum) are expressed by striatal cholinergic interneurons (CINs). Therefore, they often function as auto-receptors. We also found that the deletion of beta2* nAChRs in striatal neurons has functional consequences: it leads to an increase in the activity of striatal projection neurons, increased sensitivity to the stimulant drug amphetamine and changes in social and explorative behavior.
Striatal CINs, although they are low in numbers, are very influential in their control of the striatum and therefore it is not entirely surprising that the deletion of beta2* nAChRs in CINs leads to changes in striatal activity and behavior. However, the underlying mechanisms of these changes are still unknown and they are the main focus of this research project. To understand how nAChRs control the striatum, we first want to determine the subunit composition and subcellular localization of nAChRs in CINs and how nAChRs control CINs’ electrophysiological activity and neurotransmitter release, thus influencing the activity of other striatal neuronal population.
As mentioned above, the expression of nAChRs by striatal neurons is rare and rather specific. Therefore, beta2* nAChRs expressed by CINs can potentially serve as a tool allowing us to control the activity of CINs without affecting other neuronal populations in the striatum. Such specific control of CINs’ activity could be used in therapy of a broad range of neuropsychiatric disorders including Parkinson’s disease, dyskinesias or drug addiction.
