Abstract
Cognitive impairments and psychiatric symptoms affect up to half of patients with temporal lobe epilepsy and are often more detrimental to their quality of life than the seizures themselves. Evidence indicates that the neurobiology of epileptogenesis shares common pathophysiological mechanisms with psychiatric comorbidities. However, these mechanisms and how they relate to specific behavioral alterations are unclear. We hypothesized that a dysfunctional communication between the hippocampus and the prefrontal cortex, as a consequence of epileptogenesis, would be linked to behavioral and cognitive symptoms observed in the comorbidities of temporal lobe epilepsy. Here, we performed a multilevel study to investigate behavioral, electrophysiological, histopathological, and neurochemical long-term consequences of early-life Status Epilepticus in male rats. We found that adult animals submitted to early-life seizure (ELS) presented behavioral alterations typically found in animal models of psychosis, such as working memory deficits, hyperlocomotion, reduction in sensorimotor gating, and sensitivity to psychostimulants. Surprisingly, cognitive deficits were linked to an aberrant increase in hippocampus-prefrontal cortex (HPC-PFC) long-term potentiation (LTP) while sensorimotor alterations were associated with increased neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Noteworthy, ELS rats did not exhibit neuronal loss. Furthermore, ELS rats displayed impaired HPC-PFC theta-gamma coordination and an abnormal brain state during active behavior oddly similar to rapid eye movement (REM) sleep oscillatory dynamics. Our results point to impaired HPC-PFC functional connectivity as a possible pathophysiological mechanism by which an epileptogenic insult can cause cognitive deficits and psychosis-related manifestations even without structural damage, bearing translational implications for understanding and monitoring psychiatric comorbidities in epilepsy.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest The authors declare no competing financial interests.
This version of the manuscript has been updated with four additional figures that provide a more comprehensive illustration of the results. Furthermore, an extended methods description and an expanded discussion have also been included to provide a more detailed account of the research.
