The goal of this proposal is to elucidate the roles of the p42/44 Mitogen-Activated Protein Kinase (MAPK) pathway effectors Ribosomal S6 Kinase (RSK) and Mitogen/Stress activated Kinase (MSK) as regulators of excitotoxic cell death and aberrant structural plasticity in the hippocampus. Traumatic brain injury-induced cell death and alterations in synaptic architecture are likely to be underlying events leading to an array of cognitive disorders and the development of epilepsy. Importantly, there is a fundamental unresolved question regarding the signaling events that couple traumatic brain injury to cell death and structural remodeling. Based on recent work by others, our published findings, and the preliminary data reported here, we propose that RSK and MSK are both neuroprotective and couple traumatic brain injury to structural remodeling. Furthermore, we hypothesize that RSK and MSK function through distinct transcriptional and post-translational mechanisms to regulate these processes. To test this hypothesis, we have assembled a novel set of transgenic mice, knockout mice, and an array of screening assays.
In Aim 1 we will use the pilocarpine model of status epilepticus (SE) to systematically test the role of MSK as a regulator of SE-induced cell death. We propose that a MSK-CREB signaling cassette plays a key role in cell viability. Specific mechanisms of MSK-CREB- dependent neuroprotection, including the inducible expression of detoxifying enzymes and miRNAs will be examined.
In Aim 2 we propose to test the role of RSK in neuroprotection against SE-induced cell death. At a mechanistic level, we will examine the role of RSK as a regulator of pro-apoptotic signaling pathways.
In Aim 3, we propose to determine whether MSK and RSK signaling couple traumatic brain injury to aberrant structural plasticity in the hippocampus. A good deal of work has implicated the MAPK pathway as a regulator of activity- dependent dendrite and axon plasticity, however, the role of the MAPK pathway as a regulator of pathophysiologically-induced structural remodeling has not been systematically addressed in vivo. Here we propose to test the hypotheses that RSK stimulates injury-induced axon growth and that MSK couples injury to changes in dendrite structure. The proposed studies will provide novel and definitive data sets, which in turn, could lay the foundation for the development of new therapeutic approaches designed to 'uncouple' SE (and other forms of traumatic brain injury) from its long-term pathophysiological sequelae (e.g., epileptogenesis and cognitive impairments).
The goal of this work is to identify the underlying molecular signaling events that regulate the sensitivity of hippocampal neurons to traumatic brain injury. The hippocampus is a region of the brain that plays a critical role in higher cognitive functions, and the loss of hippocampal neurons and pathological 'rewiring' of neuronal networks leads to an array of disorders, including depression and learning/memory deficits and the development of epilepsy. Our research will provide insights into the potential therapeutic value of manipulating discrete cellular signaling pathways to avert trauma-induced neuronal death and aberrant 'rewiring' of neuronal networks.
