Neurodevelopmental function of Beta1-integrin-mediated signaling events in the prefrontal cortex

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PROJECT SUMMARY: Adolescence is characterized by massive synaptic pruning and structural stabilization in the prefrontal cortex (PFC). Given that ~50% of “adult” mental health disorders initially present during adolescence, investigating factors mediating this dramatic structural change could inform disease vulnerabilities or etiologies. Genome-wide association studies implicate ITGB1, the gene encoding β1-integrin, in disorders such as schizophrenia. In hippocampal CA1, stimulation of β1-integrin by extracellular matrix proteins stabilizes dendrites and synapses starting in adolescence. We recently observed that selective reduction of Itgb1 in the medial PFC (mPFC) has developmentally-selective consequences also, with adolescent-onset knockdown causing anhedonic-like and risk-taking behaviors. Meanwhile, adult-onset knockdown has no such effects. Given that the mPFC undergoes structural remodeling during adolescence – and is dysregulated in psychiatric illnesses – clarifying the role of β1-integrin in mPFC development may provide insight into disease etiology. I hypothesize that β1-integrin is necessary for the structural stabilization – referring here to the process by which dendritic spines are retained and escape pruning – of excitatory mPFC neurons throughout adolescence, and that this stability is necessary for the proper development of mPFC-regulated behaviors. My first aim investigates the impact of β1-integrin on mPFC neurodevelopment and function. I will selectively reduce neuronal Itgb1 in the mPFC (prelimbic subregion) of pre-adolescent mice. I will then image layer V neurons – which receive input from subcortical regions involved in mPFC-dependent decision making and mood regulation – throughout adolescence and reconstruct dendritic spines in 3D to delineate developmental trajectories. I will next selectively reduce Itgb1 in layer V neurons and identify consequences in sensorimotor gating, social interaction and recognition, and goal-directed decision making. I hypothesize that Itgb1 deficiency will cause dendritic spine loss on layer V neurons, triggering behavioral abnormalities. Neuronal β1-integrin signaling partners include Abl2/Arg kinase, cortactin, and ROCK2, which regulate actin polymerization. In my second aim, I will pharmacologically stimulate or inhibit (as appropriate) each of these factors during a key period of mPFC development, vs. when dendritic spine densities are relatively stable by comparison. I hypothesize that some or all of these pharmacomanipulations, when administered during this key period, will correct the behavioral abnormalities observed in Itgb1-deficient mice. Impact: The function of β1-integrin in the mPFC is unknown, despite β1-integrin linkage with neuropsychiatric disease and neurodevelopmental processes in other brain regions. Understanding the neurobehavioral functions of β1-integrin in the adolescent mPFC may provide insight into novel therapeutic approaches to neurodevelopmental disorders and reveal periods during which resiliencies can be conferred.