The role of CASPR2 in central oxytocin system development

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Objectives: Oxytocin is recognized as the most important mediator of social attachment in mammals. The proposed research program will investigate development of the central oxytocin system focusing on a neural adhesion protein, CASPR2, critical for the system's development and function. Background & Rationale: Oxytocin plays a well-established role in many aspects of social behaviour, including maternal attachment and social cohesion with non-kin. It is synthesized by neurons in the hypothalamus and acts on neurons throughout the central nervous system. The development of the oxytocin system during early life is crucial for establishing a normal range of social behaviours in adolescence and adulthood. Despite this importance, the neural mechanisms that regulate the development of the central oxytocin system are not well-defined. Recent studies have implicated a neural adhesion protein, CASPR2, in the development of the oxytocin system. CASPR2 is involved in dendritic development, synaptogenesis, and K+ channel clustering. Furthermore, mice genetically engineered to lack CASPR2 have low brain oxytocin levels and reduced social behaviour. Simply restoring spiking activity to oxytocin neurons in those mice, however, can rescue their social behaviour. Together those findings establish links between CASPR2, oxytocin system functioning, and social behaviour. Despite those links, how CASPR2 regulates development and function of the central oxytocin system remains unknown. Aims & Methods: 1. Identify the CASPR2-dependent molecular and cellular mechanisms that regulate structural and functional development of the central oxytocin system. I will test the hypothesis that CASPR2 contributes to establishing the optimal spike rate for of oxytocin neuron, thereby ensuring sufficient delivery of oxytocin to support social behaviour. I will examine the electrophysiological characteristics and morphology of oxytocin neurons in CASPR2-lacking mice and compare to wildtypes. 2. Determine whether CASPR2 expression during development or adulthood is necessary for proper function of the central oxytocin system and normal social behaviour. I will test the hypothesis that CASPR2 expression during early development is critical for regulating central oxytocin system development. I will use a mutant mouse line designed to selectively rescue CASPR2 expression during early development or adulthood, and examine whether it rescues the cellular morphology and electrophysiological properties in oxytocin neurons, as well as social impairments in CASPR2-lacking mice. Outcome: The proposed work will expand our current understanding on the development and function of the central oxytocin system. Findings from this study will provide new insights into the molecular and cellular mechanisms of social behaviour development and further define the critical time point(s), which may be beneficial to designing intervention strategies for infants with social developmental delays.