While much research has been done in an attempt to understand the neurophysiological mechanisms underlying epileptiform activity in the nature nervous system, comparatively few attempts have been made to study epileptogenesis in immature brain. Clinical observations support the premise that the epileptogenic properties of the central nervous system vary dramatically during development. It has been postulated that the hippocampus is one area of the immature brain which is unusually susceptible to seizures. During our initial studies, we found that hippocampal slices from rats 9-19 days of age have a pronounced capacity to generate prolonged (20-30 sec) synchronized afterdischarges when exposed to the convulsant, penicillin. During the course of these discharges individual CA3 pyramidal cells undergo a sustained depolarization. A slow negative field potential is recorded simultaneously at a distinct site in the proximal portion of the basilar dendritic layer. This observation and others led us to suggest that the sustained depolarization is the product of excitatory synaptic events taking place in the basilar dendrites. Results of our recent studies support this hypothesis. Local application of excitatory amino acid antagonists to this dendrite layer selectively abolished the sustained depolarization and blocks seizure discharging. In the absence of convulsant drugs, small localized negative field potentials (microfield potentials) are recorded at the same site in the basilar dendrites as is the slow potential associated with synchronized afterdischarges whenever the microfields are recorded. Vitually every cell in the vicinity receives a burst of postsynaptic potentials. Preliminary experiments suggest the pharmacologic sensitivity of these fields, and presumably the coincident epsps, is the same as that of the sustained depolarization. Microfields are not recorded in mature hippocampus in vitro. Nor are prolonged penicillin induced seizure-like discharges recorded. Thus, it seems possible that an augmentation in local circuit excitatory synaptic transmission during this period in hippocampal development could play a major role in its pronounced capacity for seizures. The research proposed here will study the frequency and types of synaptic interaction that occur between neurons in he CA3 subfield of 1-2-week-old rat hippocampus. Experiments will further test the hypothesis that the sustained depolarization of seizure-like discharges is a separate physiologic process and that it is synaptically mediated.

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National Institute of Neurological Disorders and Stroke (NINDS)
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Nishimura, Masataka; Casanova, J R; Swann, John W (2017) The Impact of Electrographic Seizures on Developing Hippocampal Dendrites Is Calcineurin Dependent. eNeuro 4:
Frost Jr, James D; Le, John T; Lee, Chong L et al. (2015) Vigabatrin therapy implicates neocortical high frequency oscillations in an animal model of infantile spasms. Neurobiol Dis 82:1-11
Casanova, J R; Nishimura, Masataka; Swann, John W (2014) The effects of early-life seizures on hippocampal dendrite development and later-life learning and memory. Brain Res Bull 103:39-48
Lugo, Joaquin N; Swann, John W; Anderson, Anne E (2014) Early-life seizures result in deficits in social behavior and learning. Exp Neurol 256:74-80
Weston, Matthew C; Chen, Hongmei; Swann, John W (2014) Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures. Front Mol Neurosci 7:1
Casanova, J R; Nishimura, M; Le, J et al. (2013) Rapid hippocampal network adaptation to recurring synchronous activity--a role for calcineurin. Eur J Neurosci 38:3115-27
Weston, Matthew C; Chen, Hongmei; Swann, John W (2012) Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J Neurosci 32:11441-52
Frost Jr, James D; Lee, Chong L; Le, John T et al. (2012) Interictal high frequency oscillations in an animal model of infantile spasms. Neurobiol Dis 46:377-88
Nishimura, Masataka; Gu, Xue; Swann, John W (2011) Seizures in early life suppress hippocampal dendrite growth while impairing spatial learning. Neurobiol Dis 44:205-14
Frost Jr, James D; Lee, Chong L; Hrachovy, Richard A et al. (2011) High frequency EEG activity associated with ictal events in an animal model of infantile spasms. Epilepsia 52:53-62

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