Using glutamatergic pharmacotherapy to optimize TBI recovery

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): Plasticity, the ability of the brain to modify itself in response to its environment, is fundamental to normal development and cognition. Changes in neural activation have important consequences and can interfere with normal plasticity. Traumatic brain injury (TBI) is the single largest cause of death and disability in children and young persons, and leads to developmental delays and cognitive deficits. Experimental studies have shown that perturbations of excitatory neurotransmission occur after TBI in the immature rat, and that these mechanisms may underlie subsequent impairments of environmental neuroplasticity. Recent investigations have delineated a dichotomous role for activation of the N-methyl-D-aspartate receptor (NMDAR), the predominant excitatory neurotransmitter receptor in the brain. Synaptic activation of NMDARs promotes plasticity and cell survival, while extrasynaptic activation impairs plasticity and enhances apoptotic neuronal death. This proposal hypothesizes that glutamatergic pharmacotherapy will restore disrupted molecular and physiological activation after developmental/pediatric TBI, and that treatment efficacy can be monitored using pharmacological MRI (phMRI) as a noninvasive biomarker. This goal will be achieved through the following three specific aims: 1) To measure the balance of critical molecular markers of plasticity and cell death, and establish the translational relationship between these mechanisms and quantifiable physiological functions such as regional cerebral blood volume changes (as measured using phMRI) and behavioral performance, 2) To enhance post-injury plasticity using D-cycloserine, an NMDAR co-agonist, and show specificity for this mechanism by blocking the DCS effect with an NMDAR antagonist, and 3) To restore experience-dependent plasticity after developmental TBI using rational glutamatergic pharmacotherapy. This basic science proposal has implications for future clinical/translational studies, particularly through the development of a noninvasive physiological biomarker (phMRI), and through treatment with an agent already approved for clinical use (D-cycloserine).