Seizure-induced alterations in synaptic architecture may be an underlying mechanism in the development of some forms of epilepsy. Of particular prominence is the remodeling of dentate gyms mossy fiber connections in patients with temporal lobe epilepsy. What are the signaling events elicited by excessive excitatory neurotransmission that trigger synaptic reorganization in the dentate gyrus? Although the cellular events that underlie this process are not well characterized, the similarities in the paradigms used to produce mossy fiber sprouting (and recurrent seizures) and those used to produce long-term neuronal plasticity raise the possibility that the same set of intracellular signaling pathways underlie these distinct physiological processes. Thus, we propose to examine whether signaling via the CREB/CRE transcriptional pathway couples temporal lobe seizures to mossy fiber sprouting. Interest in this plasticity-associated transcriptional pathway also comes from our preliminary data showing that seizures trigger activation of the CREB/CRE pathway, and that over-expression of activated CREB leads to robust neurite outgrowth. Thus, we hypothesize that seizures trigger CREB/CRE pathway activation, which in turn drives the expression of genes responsible for mossy fiber sprouting.
In Aim 1 will determine the temporal profile of seizure-induced CREB activation and CRE-mediated transcription in the dentate gyms. Activation will be monitored from seizure onset, through the silent period, and on into the period of recurrent seizures. The role of modulatory transcription factors and upstream kinases will also be examined.
In Aim 2 we will investigate the causal relationship between CRE-dependent transcription and mossy fiber sprouting.
In Aim 3 we will examine the expression pattern of CREB-regulated cell survival and plasticity genes and examine the role of CREB as a regulator of seizure induced neuronal precursor cell differentiation. We will also determine whether cognitive deficits resulting from status epilepticus are associated with aberrant regulation of the CREB/CRE transcriptional pathway. An understanding of the intracellular signaling events that couple seizures to synaptic remodeling should allow for the development of therapeutic approaches designed to block the development of some forms of epilepsy.
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