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.

PROJECT NARRATIVE: Fifty percent of “adult” mental health disorders initially present during adolescence. Investigating the mechanisms responsible for the proper maturation of the brain during adolescence may shed light onto disease causes and help to identify novel therapeutics. In this proposal, I will examine the function of a protein (β1-integrin) on the development of a specific region of the brain that may be vulnerable during adolescence, the prefrontal cortex, which is typically responsible for cognitive function and decision making.