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.
Traumatic brain injury reduces quality of life, because afflicted individuals are unable to process sensory information, among other neurological symptoms. The present feasibility pilot project tests whether new brain circuits, which form during the natural recovery process, are responsible for neurological dysfunction. We propose that our novel approach to pharmacologically inhibit synaptogenesis, the climactic event in the formation of these new circuits, can mitigate long-lasting post-traumatic neurological impairments, potentially in man.