Maturational Effects of Single and Multiple Early-Life Seizures on AMPA Receptors in Prepubescent Hippocampus

Abstract

The effects of single versus multiple episodes of status epilepticus on the expression of AMPA receptors during a critical growth spurt are unknown. To determine whether the pattern of hippocampal AMPA receptor subunit expression depends upon the age of the animal, timing and number of perinatal seizures, we characterized maturational changes in AMPA receptor protein levels of the hippocampus with immunohistochemistry and Western blotting in rats of juvenile ages with and without a history of neonatal seizures. Kainic acid (KA) was used to induce a single episode of status epilepticus (1 × KA) in rats on P20 or P30. Animals with a history of multiple seizures (3 × KA) were given KA on P6, P9, and then on P20 or P30. After 1 × KA, in P20 and P30 rats that are preferentially sensitive to CA1 damage, GluR1 immunoreactivity was depleted remarkably in CA1 stratum pyramidale and stratum lucidum and only morphologically healthy cells were faintly labeled. At P30, GluR2 subunit expression was nearly absent in the healthy cells and increased within the injured CA1 neuronal population. Western blot analysis confirmed that the GluR1/GluR2 ratio was decreased at P20 and further decreased at P30. A history of perinatal seizures (3 × KA) prevented the age-dependent alterations in the CA1. Except for areas of cell loss, NR1 and NR2A/B antibody labeling was relatively stable throughout the hippocampus at both ages and conditions examined. Data suggest that (i) Ca²⁺ permeable AMPA receptors may not be responsible for neuronal injury or irreversible cell loss and that (ii) the expression of AMPA receptors after status epilepticus depends upon the age of the animal, the timing of the first insult and subsequent formation of AMPA receptor subunit compositions within specific populations of hippocampal neurons.

Genetic Deletion of NR3A Accelerates Glutamatergic Synapse Maturation

“…In line with other studies [32], [38], [44], [49], [50], [51], we found that GluR1, like NR2A, also exhibits expression onset just after the first postnatal week, increases dramatically into adulthood, and is enriched in the PSD at all ages ( Figure 3d : GluR1 comparison by ages: P8, F (2,21)  = 30.729, p <0.0001; P16, F (2,15)  = 6.454, p  = 0.0113; >P40, F (2,17)  = 12.991, p  = 0.0005; GluR1 comparison by fractions: PNS, F (2,17)  = 57.918, p <0.0001; SPM, F (2,17)  = 13.702, p  = 0.0004; PSD, F (2,19)  = 40.306, p <0.0001). The preferential activity-dependent recruitment of GluR1-containing AMPARs is thought to result from LTP during the early phases of synapse maturation [52], [53], [54], [55].…”

Glutamate Receptor 1 Phosphorylation at Serine 831 and 845 Modulates Seizure Susceptibility and Hippocampal Hyperexcitability after Early Life Seizures

“…Future studies may reveal the mechanisms involved in mediating this effect on AMPAR-mediated mEPSCs following PTZ-induced seizures, compensatory changes in the excitation-inhibition imbalance may provide information regarding the specific mechanism involved in the paradoxical change observed. Animal models of seizures induced by use of chemoconvulsants in early life have shown multifactorial changes including alterations in the GABARs and AMPARs (Zhang et al, 2004; Silva et al, 2005; Friedman et al, 2007). …”

Transcriptome profiling of hippocampal CA1 after early-life seizure-induced preconditioning may elucidate new genetic therapies for epilepsy

“…In the juvenile period, we previously showed that two early neonatal seizures on P6 and P9 may serve as a preconditioning stimulus by reducing NMDA responses and injury of the CA1 subregion in P20 rats subjected to a third seizure (Liu et al ., ; Friedman et al ., ; Saghyan et al ., ). This study is the first report to examine transcriptomic profiling of the immature hippocampal CA1 with prior early‐life seizure preconditioning.…”