Studies proposed are based on the premise that brief but recurrent seizures in early-life alter the normal development of the brain. Indeed, numerous clinical observations suggest that recurrent seizures in children can lead to life-long intractable epilepsy. While this idea remains very controversial, our studies of a new model of recurrent seizures in infant rats suggest early-life seizures can produce chronic epilepsy. Nonetheless, recordings from in vitro slices are paradoxical. While CA3 networks produce robust epileptiform discharges, CA, hippocampal pyramidal cells receive intense and frequent barrages of GABAA receptor-mediated ipsps. We interpret this augmented inhibition as a compensatory mechanism used by the developing brain to counter the hyperexcitability that arises in hippocampal area CA3. If this is true, then an understanding of the developmental processes that produce augmented inhibition in area CA, might lead to therapies that would reduce or even eliminate chronic epilepsy. Studies proposed here are guided by single unifying hypothesis: that the maturation of hippocampal inhibitory interneurons is regulated by neuronal activity and specifically by GABAA-receptor-mediated synaptic transmission. Results of previous studies have shown that transient networks of GABAergic neurons exist in neonatal hippocampus. These cells excite each other since GABA is a depolarizing neurotransmitter is early-life. Thus, they produce intense network-based discharges. These transient networks likely subserve essential functions in the genesis of hippocampal circuitry. In this application, we hypothesize that as these GABAergic neurons excite each other they also delay their own maturation. In effect, temporarily preventing the differentiation of inhibitory interneurons until rudimentary circuits can be formed. Intracellular calcium transients, triggered by activation of GABAA receptors, likely mediate this effect. Restriction of dendritic growth is one proposed manifestation of GABA's actions. In contrast, by the second postnatal week, when GABAA synaptic potentials become hyperpolarizing, the network-based discharging disappears and dendritic growth and interneuron differentiation occurs. We further propose that seizures in early-life enhance the growth of inhibitory interneurons by inducing the synthesis of BDNF in hippocampal pyramidal cells. BNDF has been shown to suppress GABAergic synaptic transmission. Experiments will employ whole cell patch clamp recordings, reconstructions of individual neurons and time-lapse fluorescence videomicroscopy o growing dendrites to explore these ideas. The newly created GAD-EGFP transgenic mouse that selectively expresses EGFP in a subset of hippocampal inhibitory interneurons will be an important experimental tool in these studies.
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