Inhibition of synaptogenesis mitigates late-onset post-traumatic morbidity in rat

描述（由申请人提供）：尽管采取了预防措施（例如，头盔和安全带），创伤性脑损伤（TBI）以惊人速度发生，并经常导致 创伤性神经损伤，包括感觉灵敏度。没有有效的治疗方法可以消除TBI的神经后果。我们的长期目标是通过操纵损伤诱导的电路重组来减轻创伤后发病率（迟发性，功能获得性神经损伤）。目前的试点可行性项目探讨了新的概念，突触是巩固适应不良电路重组的关键点 在TBI之后通过这种方式，抑制突触发生可以减少脑损伤回路的适应不良重组，从而减轻创伤后发病率;然而，同样的抑制可能会阻止从创伤后缺陷（早期发作，损伤诱导的神经功能缺损）恢复的适应性可塑性。在这些实验中，我们调查与感觉灵敏度（功能性发病率）观察到的晶须刺激，开发超过28天的啮齿动物模型的弥漫性TBI，缺乏挫伤或空化的突触发生机制。这种感觉敏感性表明弥漫性组织病理学，可能包括回路可塑性和突触发生，沿着须丘脑-皮质回路。从机制上讲，突触发生可以通过凝血酶敏感蛋白（TSP）激活电压依赖性钙受体来发生。我们将研究血小板反应蛋白（TSP）在介导创伤后突触发生中的作用，这已被报道用于中风后的功能恢复。因此，出现了这样的假设，即须桶回路中的血小板反应蛋白介导的突触发生对于创伤后感觉敏感性的表达是必要的。作为一个必然的结果，突触可能是必不可少的损伤诱导的学习缺陷的恢复。在目标1中，我们将量化实验性弥漫性脑损伤后，随着时间的推移，突触形成和血小板反应蛋白相关的基因和蛋白质在体感须电路中的表达。结果将描绘作为药理学抑制的目标的突触变化的创伤后时期。在目标2中，我们将通过全身给予加巴喷丁（一种<$2 <$-1受体拮抗剂）来抑制突触发生，从而延长学习缺陷并减轻胡须相关的行为发病率和回路过度激活。治疗效果将支持突触发生在巩固与创伤后感觉敏感性发展相关的适应不良回路中的作用，并验证从学习缺陷中恢复的适应性可塑性。这种治疗的成功将支持向预防迟发性发病的模式转变，而不是治疗症状，从而改善无数弥漫性TBI患者的生活质量。

DESCRIPTION (provided by applicant): Despite preventative efforts (e.g., helmets and seatbelts), traumatic brain injuries (TBI) occur at a staggering rate and frequently result in post traumatic neurological impairment, including sensory sensitivity. No effective treatments are available to negate the neurological consequences of TBI. Our long term goal is to mitigate post-traumatic morbidity (late onset, gain-of-function neurological impairment) by manipulating injury-induced circuit reorganization. The present pilot feasibility project explores the novel concept that synaptogenesis is the pivotal point that solidifies maladaptive circuit reorganization after TBI. In this way, inhibition of synaptogenesis could curtail maladaptive reorganization of brain-injured circuits and thereby mitigate post-traumatic morbidity; however the same inhibition may prevent adaptive plasticity in the recovery from post-traumatic deficits (early onset, injury-induced neurological impairment). In these experiments, we investigate synaptogenic mechanisms associated with sensory sensitivity (a functional morbidity) observed during whisker stimulation that develops over 28 days in a rodent model of diffuse TBI that lacks contusion or cavitation. This sensory sensitivity is indicative of diffuse histopathology, likely including circuit plasticity and synaptogenesis, along the whisker thalamo-cortical circuit. Mechanistically, synaptogenesis can occur through the ¿2¿-1 voltage-dependent calcium receptor activation by thrombospondins (TSPs). We will investigate the role of thrombospondins (TSPs) in mediating post-traumatic synaptogenesis, which has been reported for functional recovery after stroke. Therefore, the hypothesis emerges that thrombospondin-mediated synaptogenesis in the whisker-barrel circuit is necessary for the expression of post-traumatic sensory sensitivity. As a corollary, synaptogenesis may be essential for recovery from injury-induced learning deficits. In Aim 1, we will quantify synaptogenic and thrombospondin-related gene and protein expression in the somatosensory whisker circuit over time after experimental diffuse brain injury. The results will delineate the post-traumatic period of synaptic change as a target for pharmacological inhibition. In Aim 2, we will prolong learning deficits and mitigate whisker-related behavioral morbidity and circuit hyper-activation by inhibiting synaptogenesis with systemic administration of gabapentin (an ¿2¿-1 receptor antagonist). Therapeutic efficacy would support a role for synaptogenesis in solidifying maladaptive circuits associated with the development of post-traumatic sensory sensitivity and verify adaptive plasticity in recovery from learning deficits. Success of this treatment would support a paradigm shift towards prevention of late-onset morbidity, rather than treatment of the symptoms, thereby improving quality of life for countless individuals with diffuse TBI.