Defining the Role of Non-Clustered Protocadherins in Forebrain Circuit Assembly - Accurate execution of complex behaviors—such as social communication and fine motor control—depends on stereotyped patterns of reciprocal connectivity between regions of the forebrain, including the cerebral cortex, amygdala, striatum, and thalamus. While species-specific specializations exist, these connectivity patterns are largely conserved across mammals. Disruption of specific forebrain connections is implicated in many neuropsychiatric disorders. For example, dysfunction in reciprocal circuits linking the prefrontal cortex (PFC) and medial thalamus has been described in schizophrenia, autism spectrum disorder, anxiety disorders, and major depressive disorder, and is associated with cognitive and affective symptoms. Mid-fetal development, an important period of circuit assembly, has been identified as a critical window of vulnerability for psychiatric disorders. Thus, elucidating the molecular mechanisms involved in establishing forebrain circuitry is essential for understanding forebrain function in both health and disease. In our preliminary studies, we identified dynamic spatiotemporal expression of non-clustered protocadherins (ncPCDHs), including conserved enrichment of protocadherin-17 (PCDH17) in reciprocally connected forebrain regions during stages corresponding to mid-fetal human development. NcPCDHs are homophilic adhesion molecules, that localize at cell-cell contact sites including axon bundles and synapses. Previous studies in mouse models have identified roles in patterning, axon growth and guidance, and synaptic maturation, stability and function. Human genetics studies have implicated ncPcdhs in neurodevelopmental disorders thus suggesting possible involvement in neural circuit formation. Specifically, disruption of PCDH17 is significantly associated with mood disorders including major depressive disorder, bipolar disorder and anxiety disorder, cognitive function, schizophrenia, and variation in amygdala size This proposal investigates the role of ncPCDHs in the establishment of forebrain connectivity, with a specific focus on the medial PFC-enriched gene PCDH17. Our central hypothesis is that ncPCDHs mediate selective synaptic connectivity between reciprocally connected forebrain regions during critical developmental windows. First, we will characterize how cell type-, region-, and temporal-specific perturbation of PCDH17 alters connectivity of the medial frontal cortex. Second, we will characterize the regulation and function of cis-regulatory elements involved in establishing the spatially and temporally restricted expression of PCDH17. Third, we will use high-resolution expression profiling of ncPCDHs to identify potential roles in the topographical organization of reciprocal connections between the cerebral cortex and thalamus. Completion of the proposed aims will provide mechanistic insights into how forebrain circuits are wired and how their disruption could contribute to neuropsychiatric disease.
