Neonatal seizures associated with hypoxic encephalopathy are refractory to conventional AED therapy, and are associated with long term neurodevelopmental delay, cognitive impairment and epilepsy. The newborn brain is fundamentally different from the adult brain, and is uniquely susceptible to epileptic stimuli as a function of physiological hyperexcitability required for activity dependent synaptogenesis and cortical development. In the prior 15 years, this research program has generated a reliable rodent model of neonatal hypoxic seizures, identified specific age-dependent mechanisms, validated the age specific expression of these targets in human neonatal cortical tissue, and executed therapeutic trials in the rat targeted towards these mechanisms, using clinically available drugs. In our rodent models of neonatal seizures, we have shown that systemic administration of glutamate receptor antagonists for 48 hrs following seizures can prevent the long term consequences, and hence may be disease modifying. The present proposal will focus on this immediate and early post seizure window to identify rapid post-translational modifications of existing protein and regulatory mechanisms governing the translation of protein from of pre-existing mRNA that may be preventable and/or reversible.
Aim 1. To determine the time course of seizure-induced changes in ionotropic glutamate receptor function, and whether they are associated with post-translational modification of receptor subunits.
Aim 2. To establish whether post-translational modifications in AMPARs and NMDARs are merely correlated or mechanistically related to in hypoxic seizure-induced epileptogenesis in vivo and in vitro. Aiim 3. To determine whether the mammalian target of rapamycin (mTOR) signaling pathway represents a therapeutic target for prevention of hypoxic-seizure induced hyperexcitability.
Aim 4. To continue our human tissue study of maturational patterns of glutamate receptor expression and investigate whether mTOR pathway activation can be detected in postmortem human brain tissue from hypoxic term infants. Our preliminary results reveal that many of these early seizure induced changes in proteins are strikingly similar to those observed in models of synaptic plasticity. The overall hypothesis of this proposal is that these early changes represent intervention points for antiepileptogenesis, even after the seizures have been induced. A major focus for this funding period is to identify these molecular targets in this 48 hr window and intervene with available off-the-shelf drugs that are known to have modulatory activity at these targets.
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