title: Age-dependent long-term structural and functional effects of early-life seizures: evidence for a hippocampal critical period influencing plasticity in adulthood.
abstract: Neural activity promotes circuit formation in developing systems and during critical periods permanently modifies circuit organization and functional properties. These observations suggest that excessive neural activity, as occurs during seizures, might influence developing neural circuitry with long-term outcomes that depend on age at the time of seizures. We systematically examined long-term structural and functional consequences of seizures induced in rats by kainic acid, pentylenetetrazol, and hyperthermia across postnatal ages from birth through postnatal day 90 in adulthood (P90). Magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and electrophysiological methods at ⩾P95 following seizures induced from P1 to P90 demonstrated consistent patterns of gross atrophy, microstructural abnormalities in the corpus callosum (CC) and hippocampus, and functional alterations in hippocampal circuitry at ⩾P95 that were independent of the method of seizure induction and varied systematically as a function of age at the time of seizures. Three distinct epochs were observed in which seizures resulted in distinct long-term structural and functional outcomes at ⩾P95. Seizures prior to P20 resulted in DTI abnormalities in CC and hippocampus in the absence of gross cerebral atrophy, and increased paired-pulse inhibition (PPI) in the dentate gyrus (DG) at ⩾P95. Seizures after P30 induced a different pattern of DTI abnormalities in the fimbria and hippocampus accompanied by gross cerebral atrophy with increases in lateral ventricular volume, as well as increased PPI in the DG at ⩾P95. In contrast, seizures between P20 and P30 did not result in cerebral atrophy or significant imaging abnormalities in the hippocampus or white matter, but irreversibly decreased PPI in the DG compared to normal adult controls. These age-specific long-term structural and functional outcomes identify P20-30 as a potential critical period in hippocampal development defined by distinctive long-term structural and functional properties in adult hippocampal circuitry, including loss of capacity for seizure-induced plasticity in adulthood that could influence epileptogenesis and other hippocampal-dependent behaviors and functional properties.
authors.affiliation: Department of Neurology, University of Wisconsin UW Medical Foundation Centennial Building 1685 Highland Ave Madison, WI 53705, USA.
authors.forename: U
authors.initials: U
authors.lastname: Sayin
authors.affiliation: Department of Neurology, University of Wisconsin UW Medical Foundation Centennial Building 1685 Highland Ave Madison, WI 53705, USA.|Department of Medical Physics, University of Wisconsin Wisconsin Institutes Medical Research 1111 Highland Avenue Madison, WI 53705, USA.
authors.forename: E
authors.initials: E
authors.lastname: Hutchinson
authors.affiliation: Department of Medical Physics, University of Wisconsin Wisconsin Institutes Medical Research 1111 Highland Avenue Madison, WI 53705, USA.|Department of Biomedical Engineering, University of Wisconsin Room 2130 Engineering Centers Building 1550 Engineering Drive Madison, WI 53706-1609, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Meyerand
authors.affiliation: Department of Neurology, University of Wisconsin UW Medical Foundation Centennial Building 1685 Highland Ave Madison, WI 53705, USA.
authors.forename: T
authors.initials: T
authors.lastname: Sutula
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy; D003337:Corpus Callosum / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology*; D006979:Hyperthermia, Induced; D007608:Kainic Acid; D007696:Kindling, Neurologic / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D010433:Pentylenetetrazole; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D007608:Kainic Acid; D010433:Pentylenetetrazole
keywords: critical periods; dentate gyrus; developmental plasticity; epilepsy; hippocampus; in vivo imaging