Effect of age on kainate-induced seizure severity and cell death

Abstract

While the onset and extent of epilepsy increases in the aged population, the reasons for this increased incidence remain unexplored. The present study used two inbred strains of mice (C57BL/6J and FVB/NJ) to address the genetic control of age-dependent neurodegeneration by building upon previous experiments that have identified phenotypic differences in susceptibility to hippocampal seizure-induced cell death. We determined if seizure induction and seizure-induced cell death are affected differentially in young adult, mature, and aged male C57BL/6J and FVB/NJ mice administered the excitotoxin, kainic acid. Dose response testing was performed in three-four groups of male mice from each strain. Following kainate injections, mice were scored for seizure activity and brains from mice in each age group were processed for light microscopic histopathologic evaluation seven days following kainate administration to evaluate the severity of seizure-induced brain damage. Irrespective of the dose of kainate administered or the age group examined, resistant strains of mice (C57BL/6J) continued to be resistant to seizure-induced cell death. In contrast, aged animals of the FVB/NJ strain were more vulnerable to the induction of behavioral seizures and associated neuropathology after systemic injection of kainic acid than young or middle-aged mice.Results from these studies suggest that the age-related increased susceptibility to the neurotoxic effects of seizure induction and seizure-induced injury is regulated in a strain-dependent manner, similar to previous observations in young adult mice. Keywords mouse strain; excitotoxicity; kainic acid; epilepsy; cell death; aging Knowledge about the influence of aging on the susceptibility of the brain to seizure disorders is of critical importance in geriatric medicine and public health. Epilepsy is the most common neurological disorder after stroke, affecting more than 50 million persons worldwide and with a 2-3% life time risk of being given a diagnosis of epilepsy (Browne and Holmes, 2001). Currently it is well known that there is a significant incidence of epilepsy in children. However, less clearly recognized but of increasing importance is the significant incidence of epilepsy in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the elderly population. Recent studies in the United States and Europe indicate that the agespecific incidence of epilepsy is higher in those over the age of 65 years than in those in the first decade of life (Talli...

Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

“…To test this, mice received a single intraperitoneal injection with the chemoconvulsant kainate, at a dose which does not induce severe seizures in C57BL/6J mice (10mg/kg),33 followed by ECoG recording and behavioral scoring using the modified Racine score 25. While wild‐type mice only reached Racine score 2 or 3, with time Mlc1 ‐null and Glialcam ‐null mice developed more severe seizures with multiple generalized tonic‐clonic seizure events (Racine score 5a–5c; Fig 4A).…”

Repeated low-dose kainate administration in C57BL/6J mice produces temporal lobe epilepsy pathology but infrequent spontaneous seizures

“…We first investigated whether repeated low-dose KA administration results in acute cell death following SE induction. Historically, a single bolus dose of KA, administered systemically to C57 animals, does not lead to cell death in hippocampus or other epilepsy-related brain regions (McCord et al, 2008; Schauwecker, 2000, 2003; Schauwecker and Steward, 1997). However, multiple brain regions in ex-KA/VPA and ex-KA/NaCl tissue displayed FJB-positive staining ( Fig.…”

“…FluoroJade-B (FJB) staining was performed using two medial hippocampal slices per animal and batch processed similarly to published methods (McCord et al, 2008), except sections were blocked for 27 min. in 0.06% KMnO 4 and stained for dying neurons for 15 min using a 0.0004% FJB solution.…”

“…Single, bolus doses of KA result in variable rates of mortality and SE induction (Hu et al, 1998; McCord et al, 2008). Additionally, bolus doses of KA do not typically produce hippocampal cell death in C57 mice, despite the induction of SE (Chang et al, 2012; McCord et al, 2008; Schauwecker, 2000, 2003; Schauwecker and Steward, 1997), but see (Chang et al, 2012; Lee et al, 2014). Seizure-induced cell death in hippocampus may contribute to the hippocampal sclerosis commonly observed in patients with temporal lobe epilepsy (TLE) (Thom, 2009), which is modeled well in rat following either pilocarpine- or KA-induced SE (Polli et al, 2014).…”

Vulnerability of hippocampal GABA-ergic interneurons to kainate-induced excitotoxic injury during old age

“…Thus, the hippocampal circuitry in the aged hippocampus appears to be pro-excitatory and highly vulnerable to conditions such as epilepsy. Indeed, the aged hippocampus exhibits increased vulnerability to epileptic seizures after injury or exposure to excitotoxins [17][18][19].…”