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

项目总结： 青春期的特点是前额叶大量的突触修剪和结构稳定 皮层(PFC)。鉴于约50%的成人精神健康障碍最初出现在青春期， 调查导致这种戏剧性结构变化的因素可能会为疾病的脆弱性或病因提供信息。 全基因组关联研究表明，编码β1整合素的基因ITGB1与以下疾病有关 精神分裂症。在海马CA1区，细胞外基质蛋白对β-1整合素的刺激稳定 树突和突触始于青春期。我们最近观察到，Itgb1的选择性减少在 内侧PFC(MPFC)也有发育选择性的后果，青少年发病的击倒 导致类似享乐主义和冒险的行为。与此同时，成人发病的基因敲除没有这样的影响。 鉴于mPFC在青春期经历了结构重塑-并且在精神病患者中调节失调 疾病-阐明β1-整合素在mPFC发展中的作用可能有助于深入了解疾病病因。我 假设β1-整合素是结构稳定所必需的-这里指的是过程 通过这种方式，树突棘被保留并逃避兴奋性mPFC神经元的修剪 青春期，这种稳定性是mPFC调节的正常发育所必需的 行为。 我的第一个目标是研究β1-整合素对mPFC神经发育和功能的影响。这就做 选择性减少青春期前小鼠mPFC(预备区)神经元Itgb1。然后我会想象 第V层神经元--接受参与mPFC依赖决策的皮质下区域的信息 和情绪调节--贯穿整个青春期，并在3D中重建树突棘来描绘 发展轨迹。接下来，我将选择性地减少V层神经元中的Itgb1，并确定 感觉运动门控，社会互动和识别，以及目标导向的决策。我假设 Itgb1缺乏会导致V层神经元上的树突棘丢失，引发行为异常。 神经元β1-整合素信号伙伴包括ABL2/Arg激酶、Cortactin和ROCK2，它们调节 肌动蛋白聚合。在我的第二个目标中，我将用药物刺激或抑制(视情况而定)每一个 在mPFC发育的关键时期，与树突棘密度相对稳定时的这些因素 相比之下。我假设这些药物中的一部分或全部，当在这个过程中使用时 关键时期，将纠正在Itgb1缺陷小鼠中观察到的行为异常。 影响：β1-整合素在mPFC中的功能尚不清楚，尽管β1-整合素与 神经精神疾病和其他脑区的神经发育过程。了解 青春期β-1整合素的神经行为功能可能为新的治疗方法提供线索 治疗神经发育障碍的方法，并揭示了可以授予复原力的时期。

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.