Febrile seizures impair memory and cAMP response‐element binding protein activation

Abstract

The long-term effects of brief but repetitive febrile seizures (FS) on memory have not been as thoroughly investigated as the impact of single and prolonged seizure in the developing brain. Using a heated-air FS paradigm, we subjected male rat pups to one, three, or nine episodes of brief FS on days 10 to 12 postpartum. Neither hippocampal neuronal damage nor apoptosis was noted within 72 hours after FS, nor was there significant hippocampal neuronal loss, aberrant mossy fiber sprouting, or altered seizure threshold to pentylenetetrazol in any FS group at adulthood. The adult rats subjected to nine episodes of early-life FS, however, showed long-term memory deficits as assessed by the Morris water maze. They also exhibited impaired intermediate and long-term memory but spared short-term memory in the inhibitory avoidance task. Three hours after inhibitory avoidance training, phosphorylation of cAMP response-element binding (CREB) protein in the hippocampus was significantly lower in nine-FS-group rats than in controls. Furthermore, rolipram administration, which activated the cAMP-CREB signaling pathway by inhibiting phosphodiesterase type IV, reversed the long-term memory deficits in nine-FS-group rats by enhancing hippocampal CREB phosphorylation. These results raise concerns about the long-term cognitive consequences of even brief frequently repetitive FS during early brain development.

Loss of dendritic inhibition in the hippocampus after repeated early-life hyperthermic seizures in rats

“…Rats belonging to the seizure group were individually placed into a 3-l glass cylinder which was partly immersed in a water bath kept at room temperature to help prevent overheating of the walking surface (Chang et al, 2003). A hair dryer at a moderate heat setting (500 W) was used to blow hot air down from the top of the container, ∼50 cm above the head of the rat.…”

“…A hair dryer at a moderate heat setting (500 W) was used to blow hot air down from the top of the container, ∼50 cm above the head of the rat. The ambient air temperature within the container (measured at a height level with the rat's head) was kept between 46 and 49 • C (Chang et al, 2003). Temperature was measured by gentle insertion of a thermometer into the external ear canal before and after each hyperthermia/control session for every rat.…”

“…As a model of febrile seizures, hyperthermia-induced seizures in immature rats (Baram et al, 1997) were found to increase longterm seizure susceptibility and induce spontaneous seizures (Dube et al, 2010), without significant cell loss or sustained brain damage (Dube et al, 2000). Additionally, long-term behavioral changes have been reported after hyperthermic seizures (Chang et al, 2003;Dube et al, 2000Dube et al, , 2009Dube et al, , 2010. Long-term physiological changes after febrile seizure models include alteration of intrinsic membrane currents and an increased in GABA A receptor-mediated transmission in hippocampal slices in vitro (Chen et al, 1999).…”

Hypoxic–ischemic retinal injury in rat pups

“…On P33, following deep anesthesia with an overdose of chloral hydrate 500 mg/kg i.p., rats were killed. The brains and eyes were removed, weighted, fixed, and then embedded in paraffin as described previously (26). After removal of the brainstem and cerebellum, the forebrain was sectioned at the midline, and left and right hemispheric weights were determined.…”

Effects of chronic network hyperexcitability on the growth of hippocampal dendrites

“…It has been debated whether the seizures and accompany neuronal network hyperexcitability contribute to learning disabilities, since a neuropathology could be responsible for both seizures and cognitive impairments. However, recent studies in normal rodents have shown that experimentally-induced recurrent seizures can lead to spatial learning and memory deficits (Holmes et al, 1998;Huang et al, 1999;Lee et al, 2001;Chang et al, 2003). Reduced dendritic arbors following recurrent seizures would be one potential mechanism underlying such learning deficits given that dendrites are the major site of excitatory synaptic transmission and the plasticity thought to underlie formation of memories.…”