Positive allosteric modulation of cholinergic receptors in recovery after brain trauma

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 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) costs the country more than $76.5 billion a year, with an estimated 5.3 million U.S. residents living with TBI-related disabilities (CDC 2009 data). Although it is not possible to eliminate the immediate neuronal damage that occurs at the moment of TBI, it may be possible to alleviate the secondary damage that occurs hours or even weeks post-TBI, and thereby improve the brain function and quality of life of TBI survivors. However, there are currently no clinically efficacious drug therapies to tret neuronal damage secondary to TBI. Brain cholinergic mechanisms are essential to learning and memory, and these are severely impacted, both acutely and chronically, in human TBI patients and in TBI animal models. Use of acetylcholinesterase (AChE) inhibitors as a treatment strategy has met with modest clinical success; however, undesirable toxic effects of AChE inhibition have limited dosage increases. Recently, an unprecedented line of work has been opened with the development of positive allosteric modulators (PAMs) of cholinergic receptors. PAMs bind to allosteric sites where they have no effect alone, but increase the affinity and/or efficacy of endogenous acetylcholine. In the current proposal, we examine the efficacy of benzylquinolone carboxylic acid (BQCA), a PAM of the M1 muscarinic receptor which is known to have a lower incidence of undesirable side effects mediated by other cholinergic receptors subtypes M2-M5. In Aim 1, we examine the effects of 3 weeks of BQCA administration in a mouse model of focal, unilateral motorsensory cortical contusion injury (CCI) using functional outcomes of learning and memory, as well as motor function. Comparison is made for treatments initiated 3 days (subacute) or 3 weeks (subchronic) after injury. Aim 2 applies functional brain imaging to examine what cerebral circuits are affected during functional restoration following BQCA administration. Aim 3 examines sex differences in the effects of BQCA on the injured brain. Our study will be the first to explore the role of a muscarinic PAM in a TBI model. It will also for th first time present data on sex differences in cognitive and motor recovery following administration of cholinergic PAMs in the acute and subacute period after CCI. This translational study is consistent with the National Center for Medical Rehabilitation Research (NCMRR) 2006 report emphasizing the need for preclinical studies to advance neurorehabilitation. Results will lay the much needed groundwork for understanding the role of PAMs of the M1 receptor on functional recovery after TBI.