A single seizure selectively impairs hippocampal‐dependent memory and is associated with alterations in PI3K/Akt/mTOR and FMRP signaling

Abstract

SummaryObjectiveA single brief seizure before learning leads to spatial and contextual memory impairment in rodents without chronic epilepsy. These results suggest that memory can be impacted by seizure activity in the absence of epilepsy pathology. In this study, we investigated the types of memory affected by a seizure and the time course of impairment. We also examined alterations to mammalian target of rapamycin (mTOR) and fragile X mental retardation protein (FMRP) signaling, which modulate elements of the synapse and may underlie impairment.MethodsWe induced a single seizure and investigated hippocampal and nonhippocampal memory using trace fear conditioning, novel object recognition (NOR), and accelerating rotarod to determine the specificity of impairment in mice. We used western blot analysis to examine for changes to cellular signaling and synaptic proteins 1 h, 24 h, and 1 week after a seizure. We also included a histologic examination to determine if cell loss or gross lesions might alternatively explain memory deficits.ResultsBehavioral results indicated that a seizure before learning leads to impairment of trace fear memory that worsens over time. In contrast, nonhippocampal memory was unaffected by a seizure in the NOR and rotarod tasks. Western analysis indicated increased hippocampal phospho‐S6 and total FMRP 1 h following a seizure. Tissue taken 24 h after a seizure indicated increased hippocampal GluA1, suggesting increased α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor expression. Histologic analysis indicated that neither cell loss nor lesions are present after a single seizure.SignificanceThe presence of memory impairment in the absence of damage suggests that memory impairment caused by seizure activity differs from general memory impairment in epilepsy. Instead, memory impairment after a single seizure is associated with alterations to mTOR and FMRP signaling, which leads to a disruption of synaptic proteins involved in consolidation of long‐term memory. These results have implications for understanding memory impairment in epilepsy.

Neocortical and cerebellar malformations affect flurothyl-induced seizures in female C57BL/6J mice

“…Our results differ from a previous study with male C57BL/10J inbred mice, which have a greater prevalence of neocortical heterotopia and exhibit a lower seizure threshold to pentylenetetrazole (PTZ)-induced seizures (Gabel et al, 2013). While every experimental approach for seizure induction has its strengths and limitations, we used flurothyl in this study because of our extensive expertise with this approach (Lugo et al, 2014;Holley and Lugo, 2016;Holley et al, 2018;Binder et al, 2022). Moreover, flurothyl is much easier to use compared to methods requiring intraperitoneal injection, where mice often need multiple doses of chemiconvulsant to provoke a seizure or never exhibit a generalized seizure, complicating measures of latency.…”

“…The chemi-convulsant flurothyl was used to induce an acute seizure as previously described by our group (Holley and Lugo, 2016;Holley et al, 2018). Each seizure was induced under a standard fume hood inside a clear acrylic (29 × 16 × 15 cm) inhalation chamber.…”

Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions

“…However, two points follow from our observations. First, Bernard et al [89] demonstrated in a normal rat model that early life seizures reduce dendritic FMRP at/near synapses, with a corresponding shift of FMRP to the neuronal soma, despite an apparent increase in overall hippocampal FMRP [90]. Thus, the occurrence of early-life seizure creates a functional deficit of FMRP for synaptic functioning in the rat, with the corresponding reduction of cognitive function.…”

Epilepsy Surgery for Focal Cortical Dysplasia: Clinicopathological Correlates and Advances in Neuroimaging.

“…Moreover, a portion of patients present with epileptic encephalopathy. On top of the disturbances related to the structural anatomy, epileptic activity causes memory consolidation disruption 29 and in epileptic brain there is a deviation from the optimal network organisation 30,31 . Cognitive disability is not only caused by epileptic activity or the underlying pathology, but also the use of anti-epileptic drugs has negative effects, due to general dampening of neuronal signalling and consequent detrimental effects on cognitive development 32 .…”