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Abstract

Neuronal cell adhesion molecules have recently been put into the spotlight of preclinical and clinical research as potential candidates for the mediation of stress effects on brain function and behavior. The stress-induced remodeling of neuronal circuits for structural and functional changes is triggered by the reorganization of synaptic connections, a process that is potentially mediated by neuronal cell adhesion molecules. Disturbances in neuronal connectivity, induced by genetic and/or environmental influences, may cause behavioral dysfunctions related to neuropsychiatric disorders. Understanding the actions of these molecules at the synapse may thus provide insights into fundamental processes of synaptic cell adhesion and connectivity, but moreover help to elicit the molecular mechanisms underlying synapse properties and function. In this thesis, I investigated the involvement of two candidate molecules, NCAM and Neuroligin-2, in stress and social behavior. Concerning NCAM, I could show that diminished expression in the forebrain renders individuals more vulnerable to chronic stress in adulthood. In detail, I extended the knowledge about NCAM by examining the impact of a conditional NCAM-knockout on emotional and aggression-related behavior in the interplay with stress. Further, I investigated the role of neuroligin-2 in mediating the effects of early-life stress on social behavior, social cognition and aggression. Therefore, I characterized and validated an early-life stress model on alterations of social behavior in adulthood and identified neuroligin-2 as potential mediator of the stress effects and behavioral alterations. I could show that neuroligin-2 expression in the hippocampus critically impacts on social behavior, rendering it a promising target for therapeutic interventions. The findings presented in my thesis clearly demonstrate a crucial role of neuronal cell adhesion molecules in stress, social behavior, especially aggression, and social cognition, and provide an encouraging foundation for future research on novel treatment strategies for neuropsychiatric disorders based on the molecular actions and interactions of neuronal cell adhesion molecules.