Spatial learning impairments and discoordination of entorhinal‐hippocampal circuit coding following prolonged febrile seizures

Abstract

How the development and function of neural circuits governing learning and memory are affected by insults in early life remains poorly understood. The goal of this study was to identify putative changes in cortico‐hippocampal signaling mechanisms that could lead to learning and memory deficits in a clinically relevant developmental pathophysiological rodent model, Febrile status epilepticus (FSE). FSE in both pediatric cases and the experimental animal model, is associated with enduring physiological alterations of the hippocampal circuit and cognitive impairment. Here, we deconstruct hippocampal circuit throughput by inducing slow theta oscillations in rats under urethane anesthesia and isolating the dendritic compartments of CA1 and dentate gyrus subfields, their reception of medial and lateral entorhinal cortex inputs, and the efficacy of signal propagation to each somatic cell layer. We identify FSE‐induced theta‐gamma decoupling at cortical synaptic input pathways and altered signal phase coherence along the CA1 and dentate gyrus somatodendritic axes. Moreover, increased DG synaptic activity levels are predictive of poor cognitive outcomes. We propose that these alterations in cortico‐hippocampal coordination interfere with the ability of hippocampal dendrites to receive, decode and propagate neocortical inputs. If this frequency‐specific syntax is necessary for cortico‐hippocampal coordination and spatial learning and memory, its loss could be a mechanism for FSE cognitive comorbidities.

Dysfunctional Hippocampal-Prefrontal Network Underlies a Multidimensional Neuropsychiatric Phenotype following Early-Life Seizure

“…Here we observed lower theta-gamma correlations in the PFC of ELS animals, suggesting a disconnection between theta power and local coordination of PFC activity. Similarly, the prolonged febrile model of ELS also presents decreased coordination of gamma activity in the hippocampal circuits (Kloc et al, 2023 ). In addition, we also observed a flatter PFC power spectrum in ELS animals compared to the normal tilt of CTRL, which has been discussed to indicate excitation/inhibition imbalance (Gao et al, 2017 ).…”

Dysfunctional hippocampal-prefrontal network underlies a multidimensional neuropsychiatric phenotype following early-life seizure

“…Here, we observed lower theta-gamma correlations in the PFC of ELS animals, suggesting a disconnection between theta power and local coordination of PFC activity. Similarly, the prolonged febrile model of ELS also resulted in a decreased coordination of gamma activity in the hippocampal circuits ( Kloc et al, 2023 ). In addition, we also observed a flatter PFC power spectrum in ELS animals compared to the normal tilt of CTRL, which has been discussed to indicate excitation/inhibition imbalance ( Gao et al, 2017 ).…”

Do vaccines cause epilepsy? Review of cases in the National Vaccine Injury Compensation Program

“…Both the clinical and animal studies indicate that the immature brain is quite resistant, but not unaffected by the detrimental effects of FSE. Although FSE does not cause cell death in the immature brain, morphological and functional changes occur 94,100–102 that may culminate in temporal lobe seizures. However, both the clinical and animal data suggest that the development of epilepsy following FSE occurs rarely.…”