Mechanisms of Persistently Decreased Inhibition of Area CA1 of the Hippocampus Following Perinatal Hypoxia-induced Seixures
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Hypoxia in the neonate is one of the leading causes of encephalopathy and seizures. Sadly, a significant subset of these children will acquire epilepsy, as their risk increases several-fold even with recovery from the initial encephalopathy. Epilepsy can be debilitating and potentially fatal, and can be considered as a condition of hyper-excitable and hyper-synchronistic neural circuitry. Cellular and molecular changes consequent to neonatal seizure-inducing hypoxia are not fully understood, but multiple pro-epileptogenic candidate mechanisms exist. For example, acutely decreased inhibition has been shown at 1 hour post-hypoxia induced seizures, but it is unknown whether this effect is persistent. Such persistent effects on inhibition could promote the development of epilepsy. We designed three specific aims to determine mechanisms of persistently decreased inhibition of area CA1 of the hippocampus following perinatal hypoxia-induced seizures. Specific Aim One was to determine whether the acute (P10) decrease in GABA mediated inhibitory currents, IPSCs, persists beyond the initial 24 hours reported previously. We hypothesized that there would be a persistent increase in inhibition at least one week post hypoxia. Whole-cell voltage-clamp data indicates persistently decreased action potential-dependent GABA-mediated inhibitory post synaptic currents that may possibly be due to decreased interneuron firing. Specific Aim Two was to determine whether there are persistent changes to the composition/expression of the GABAA receptor in hippocampus. We hypothesized that there would be persistent decreases in the overall expression and or composition of the GABAA receptor. Western blot analysis suggests that no change in the expression of α1, α2, β2/3 or γ2 GABA_(A) subunits occurs, at any time point studied, following perinatal hypoxia-induced seizures. Specific Aim Three was to determine whether there are persistent changes in calcineurin expression/activity. We hypothesized that there would be an increase in hippocampal calcineurin expression and/or activity persistently following hypoxia-induced seizures. Western blot data suggests that no change in the expression of calcineurin occurs beyond the initial 24 hours post hypoxia-induced seizures previously reported. Furthermore, calcineurin activity did not increase at 24 hours and 48 hours post hypoxia-induced seizures. Preliminary data suggests activation of an alternative enzymatic pathway, possibly Interleukin-1 receptor dependent activation of casein kinase II, possibly contributing to altered GABAergic inhibition of area CA1 of the hippocampus.
Justice, Jason Arnold (2013). Mechanisms of Persistently Decreased Inhibition of Area CA1 of the Hippocampus Following Perinatal Hypoxia-induced Seixures. Doctoral dissertation, Texas A & M University. Available electronically from