The role of the clustered protocadherins in neural circuit formation and implications for neurodevelopmental disorders

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PROJECT SUMMARY Functional circuits between the approximately 80 billion human neurons connecting trillions of synapses in the human brain must be established during development. Failure to organize proper neural circuits has been linked to neurodevelopmental disorders such as autism and neuropsychiatric diseases. During development, individual neurons extend highly branched neurites that innervate the surrounding territory with minimal overlap. Moreover, some neuronal subtypes, such as serotonergic and dopaminergic neurons, must tile throughout receptive fields in the brain to ensure that their neurites do not cross over or clump with sister or neighboring neurites or other neurons of the same type. Proper wiring of these neuronal cell types is required for the physiological distribution of serotonin and dopamine in the brain. In mammals, a family of highly diverse cell-surface homophilic proteins, the clustered protocadherins (cPcdh), provides each neuron a unique cell-specific identity required for normal neural circuit assembly. The protocadherin gene cluster encompasses three distinct gene clusters, designated ,  and and previous studies from our laboratory demonstrated that a single gene in the Pcdh gene cluster (Pcdhc2) is required for normal serotonergic wiring in mice. Deletion of the entire Pcdh gene cluster or Pcdhc2 alone led to clumping and crossing of serotonergic neurons (a tiling defect), and altered behavior (depression and enhanced fear response). These findings provided significant advances in defining a role for individual cPCDH proteins in specific neuronal subtypes; however, a role for the exclusive expression of specific cPcdh isoforms in other neuronal subtypes and the mechanisms used to execute self-avoidance and tiling remain poorly understood. Here, we propose to address these gaps in understanding by studying the role of the cPcdh gene cluster in the wiring of dopaminergic neurons and behavior in mice. In Aim 1, we will survey the transcriptional landscape of cPcdh isoforms across midbrain dopaminergic neurons in mice. In Aim 2, we will investigate the role of Pcdhβ cluster on dopaminergic wiring, dopamine release and reward prediction and novelty behaviors. In Aim 3, we will examine the mechanism by which PCDHβ proteins, establish proper DAN organization. Together, these new directions should provide novel insights into the molecular logic underlying neural circuit formation and have implications for neurodevelopmental and neuropsychiatric disorders.