Dysfunctional Hippocampal-Prefrontal Connectivity without Neuronal Loss Is Associated with Psychotic-Like Behaviors Following Early-Life Seizure

Cognitive impairments and psychiatric symptoms affect up to half of temporal lobe epilepsy patients 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 (HPC) and the prefrontal cortex (PFC), 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 hyperlocomotion, reduction in sensorimotor gating, working memory deficits, and sensitivity to psychostimulants. Noteworthy, ELS rats did not exhibit neuronal loss. Instead, sensorimotor alterations were associated with increased neuroinflammation, as verified by glial fibrillary acidic protein (GFAP) expression, and altered dopamine neurotransmission. Surprisingly, cognitive deficits were linked to an aberrant increase in HPC-PFC long-term potentiation (LTP). Furthermore, ELS rats displayed an abnormal brain state during active behavior characterized by oscillatory dynamics oddly similar to REM sleep. Our results point to impaired hippocampal-prefrontal network dynamics as a possible pathophysiological mechanism by which an epileptogenic insult can cause behavioral changes without neuronal loss. These convergent patterns of dysfunctional activity between epileptogenesis and psychosis bear translational implications for understanding psychiatric and cognitive comorbidities in epilepsy. ### Competing Interest Statement The authors have declared no competing interest.