Increasing evidence suggests that abnormalities in synaptic transmission in disease-relevant brain circuits likely contribute to the etiologies that underlie neuropsychiatric disorders. Thus, the essential question: how are circuit-level synaptic properties specified and maintained? Molecularly, synaptic cell adhesion molecules (SCAMs) are prime candidates because they often span the pre- and post-synaptic membrane, physically link both terminals and initiate intracellular signaling cascades to recruit key synaptic molecules to the synapse. Moreover, genomic studies have mutations in many of these molecules that are associated with psychiatric diseases. Mutations unique to neurexin-3 (Nrxn3), an essential presynaptic SCAM, have been linked to schizophrenia (SZ) and drug addiction in humans. These disorders are associated with an enormous social and economic burden and share a common pathophysiological basis of dopamine dysregulation due to hyperactivity in the ventral subiculum (vSub) - nucleus accumbens (NAc) shell circuit. Hyperactivity of this circuit can be caused by changes in synaptic transmission in the vSUB-NAc projection circuit or in the ventral subiculum local circuit. Despite the obvious importance of the vSUB-NAc shell circuit, a molecular and synaptic understanding of this circuit is lacking. Thus, the hypothesis that neurexin-3 plays critical, cell-type specific and nonredundant functions to shape projection and local subicular circuitry that are essential for dopamine regulation will be tested in this proposal.
Aim 1 will investigate how Nrxn3 is utilized by the two types of vSUB projection neurons that innervate D1R or D2R expressing MSNs in the NAc shell. A fundamental understanding of the cell-type specific connectivity between the vSUB and NAc shell and how Nrxn3 shapes these excitatory synaptic properties is unexplored; thus, the dissection of cell-type specific pre- and post-synaptic functions of subicular neurons within this disease circuit may open new avenues for treatment strategies.
Aim 2 will build on preliminary RNA-seq data generated during the K99 training phase that revealed Nrxn3 isoform expression is strongly differentially regulated in two distinct subsets of hippocampal GABAergic interneurons. We will dissect the poorly understood cell-type specific local circuit in the subiculum and how discrete Nrxn3 gene products are utilized to shape cell-type specific synaptic transmission.
Aim 3 will characterize the transcriptional profiles of electrophysiologically distinct pyramidal neurons in the subiculum using a single-cell RNA-seq approach. This unbiased approach will allow for the identification of differential, cell-type specific disease-relevant SCAM expression for future study and for the generation of genetic tools to facilitate the dissection of the subiculum. The molecular interrogation of Nrxn3 in the local and projection subicular circuit will provide the first insight into the disease-relevance of neurexin-3 and will further our understanding of neurexin function in general and will lay the foundation for future studies.
Due to a lack of understanding regarding the synaptic basis underlying Schizophrenia and reward-seeking behavior, the effectiveness of current pharmacological therapies is curtailed by unwanted side effects. Recent genome screenings have identified mutations in the presynaptic cell adhesion molecule, neurexin-3 that are associated with Schizophrenia and reward-seeking behavior, however, the biological significance of neurexin-3 in circuits of disease remain unexplored. We here propose to use a novel neurexin-3 model and cutting-edge technologies to study how neurexin-3 functions to shape cell-type specific synaptic properties in the brain circuit closely associated with these devastating neuropsychiatric disorders with the hope that new therapeutic avenues might be identified.
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