While much research has been done in an attempt to understand the neurophysiological mechanisms underlying epileptiform activity in the mature 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 suseptible 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) afterdischarges when exposed to the convulsant penicillin. More recently we have found that relatively low frequency (2Hz) repetitive orthodromic stimulation of immature CA3 neurons bathed in normal media also results in prolonged afterdischarges. During the onset of both types of ictal episodes, we have recorded a slow negative field potential in stratum oriens just below the cell body layer (the infrapyramidal zone). In addition, a virtually identical slow potential occurs spontaneously in this region. This event is coincident with an intracellularly recorded epsp. In pencillin-containing media, intracellular recordings have revealed a depolarizing afterpotential which follows the downstroke of the depolarization shift (DS) and which is coincident with the infrapyramidal zone slow negative potential. Thus we have hypothesized that this afterpotential is a summated epsp. During pencillin-induced epileptiform discharges we have recorded very large increases in [K+]o in the CA3 region of immature slices. These changes are largest in the infrapyramidal zone. During our recent recordings of spontaneous slow negative field potentials in this region, we have also recorded transient increases in [K+]o, which follow these fields one-for-one. These and other recordings have led us to hypothesize that the increase in K+ recorded in the infrapyramidal zone is a direct product of the epsp which we have suggested mediates the DS depolarizing afterpotential. Thus this epsp may mediate seizure generation not only through its ability to directly depolarize immature CA3 pyramidal cells but also through K+ accumulation extracellularly. The research proposed here will attempt to test these hypotheses and demonstrate a central role for local excitatory interactions in seizure generation in the CA3 region of immature hippocampus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS018309-05
Application #
3398347
Study Section
Neurology A Study Section (NEUA)
Project Start
1982-04-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
New York State Department of Health
Department
Type
DUNS #
002436061
City
Menands
State
NY
Country
United States
Zip Code
12204
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

Showing the most recent 10 out of 62 publications