The long term objectives of this project are to understand the relationship between seizures and brain development. As shown in the progress report, we have recently discovered an exception to the general rule that the immature brain is selectively resistant to seizure-induced damage. The goals for the upcoming period of this project will be to explore the limits and significance of that exception. This will be done in four general areas: (A) seizure induced neuronal injury, ( of inhibition in the dentate gyrus, CC) epileptogenicity, (D) induction of sprouting. A. We will establish by quantitative histological methods whether sustained perforant path stimulation induces irreversible neuronal loss in 15 day old rats, and will compare the distribution and time course of damage to that observed in the adult after similar stimulation. We expect that similar durations of stimulation will induce less severe legions at younger ages, and that this resistance will not be absolute. We will define by immunocytochemistry and in situ hybridization the subpopulations of hila neurons which sustain damage, and expect a different distribution as a function of age. We will treat the animals with blockers of NMDA and non NMDA glutamate receptors.a We expect to protect selective subpopulations with those agents. We will test the effect of SE on the immature brain in the rabbit, a species which is very immature at birth, the guinea pig, which is very mature at birth; and the marmoset which is intermediate. B. We will study the effect of sustained perforant path stimulation on paired pulse inhibition in the dentate gyrus. We will follow the time course of this loss of inhibition during the recovery period and the period of sprouting. C. We will study the epileptogenicity of lesions. We expect that spontaneous seizures and accelerated kindling will be observed in animals following perforant path stimulation of sufficient severity to induce neuronal loss. 0. We will study sprouting by Timm stain, and by immunocytochemistry and in situ hybridization studies of GAP 43, NAP2, and GFAP. We will also study the induction of neurotrophins and of their receptors. These studies will define the risk of hippocampal damage from epileptic seizures during early childhood in several species, and should help clinicians to understand the basic principles that underlay treatment of non convulsive seizures.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology A Study Section (NEUA)
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Jacobs, Margaret
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Thompson, Kerry W; Suchomelova, Lucie; Wasterlain, Claude G (2018) Treatment of early life status epilepticus: What can we learn from animal models? Epilepsia Open 3:169-179
Dingledine, Raymond; Coulter, Douglas A; Fritsch, Brita et al. (2017) Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci Data 4:170061
Suchomelova, L; Lopez-Meraz, M L; Niquet, J et al. (2015) Hyperthermia aggravates status epilepticus-induced epileptogenesis and neuronal loss in immature rats. Neuroscience 305:209-24
Wasterlain, Claude G; Naylor, David E; Liu, Hantao et al. (2013) Trafficking of NMDA receptors during status epilepticus: therapeutic implications. Epilepsia 54 Suppl 6:78-80
Naylor, David E; Liu, Hantao; Niquet, Jerome et al. (2013) Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiol Dis 54:225-38
Wasterlain, Claude G; Gloss, David S; Niquet, Jerome et al. (2013) Epileptogenesis in the developing brain. Handb Clin Neurol 111:427-39
Wasterlain, Claude G; Stöhr, Thomas; Matagne, Alain (2011) The acute and chronic effects of the novel anticonvulsant lacosamide in an experimental model of status epilepticus. Epilepsy Res 94:10-7
Wasterlain, Claude G; Baldwin, Roger; Naylor, David E et al. (2011) Rational polytherapy in the treatment of acute seizures and status epilepticus. Epilepsia 52 Suppl 8:70-1
Lopez-Meraz, Maria-Leonor; Wasterlain, Claude G; Rocha, Luisa L et al. (2010) Vulnerability of postnatal hippocampal neurons to seizures varies regionally with their maturational stage. Neurobiol Dis 37:394-402
Lopez-Meraz, Maria-Leonor; Niquet, Jerome; Wasterlain, Claude G (2010) Distinct caspase pathways mediate necrosis and apoptosis in subpopulations of hippocampal neurons after status epilepticus. Epilepsia 51 Suppl 3:56-60

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