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

描述(申请人提供)：尽管采取了预防措施(如头盔和安全带)，但创伤性脑损伤(TBI)的发生率令人震惊，并经常导致POST 创伤性神经损伤，包括感觉敏感度。目前还没有有效的治疗方法来否定脑外伤的神经后果。我们的长期目标是通过操纵损伤诱导的回路重组来减轻创伤后的发病率(起病晚，神经功能受损)。目前的试点可行性项目探索了一种新的概念，即突触发生是固化适应不良回路重组的关键点。 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非适应性重组，从而减轻创伤后的发病率；然而，同样的抑制可能会阻止创伤后缺陷(早期发病，损伤所致的神经损伤)恢复的适应性可塑性。在这些实验中，我们研究了与感觉敏感性(一种功能性发病率)相关的突触发生机制，在缺乏挫伤或空化的弥漫性脑损伤啮齿动物模型中，在28天的胡须刺激期间观察到了这种机制。这种感觉敏感性是沿着胡须丘脑-皮质回路的弥漫性组织病理学的指标，可能包括回路可塑性和突触发生。从机制上讲，突触发生可以通过血小板反应素(TSPs)激活电压依赖性的钙受体来实现。我们将研究血栓反应蛋白(TSPs)在介导创伤后突触形成中的作用，这已被报道为卒中后功能恢复。因此，出现了这样的假设，即血栓反应蛋白在胡须桶环路中介导的突触发生对于创伤后感觉敏感性的表达是必要的。作为推论，突触的形成可能是从损伤诱导的学习缺陷中恢复的关键。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，突触生成和血栓反应蛋白相关的基因和蛋白在体感胡须回路中的表达。这一结果将描绘出创伤后突触改变的时期，作为药物抑制的目标。在目标2中，我们将通过全身应用加巴喷丁(一种2受体拮抗剂)来抑制突触发生，延长学习障碍，减轻胡须相关的行为发病率和电路过度激活。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方面的作用，并验证学习缺陷恢复的适应性可塑性。这种治疗的成功将支持将范式转变为预防迟发性发病率，而不是治疗症状，从而改善无数弥漫性脑外伤患者的生活质量。

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.