# Neonatal Febrile Seizures in Rats Induce Long-Term Region-Specific Alterations in the Glutamatergic System of Hippocampal–Prefrontal Circuits and Lead to Behavioral Deficits

## TL;DR

Neonatal febrile seizures in rats cause long-term changes in brain regions linked to anxiety and emotional regulation, leading to behavioral issues in adulthood.

## Contribution

This study is the first to show region-specific, long-term glutamatergic system alterations and behavioral deficits following neonatal febrile seizures.

## Key findings

- Neonatal febrile seizures cause region-specific molecular changes in the glutamatergic system in the ventral hippocampus and medial prefrontal cortex.
- Behavioral outcomes include hyperanxiety and locomotor deficits, but working memory and sociability remain unaffected.
- The findings suggest a neurobiological mechanism linking early-life febrile seizures to increased anxiety risk.

## Abstract

This study provides the first comprehensive analysis of long-term, region-specific changes in the entire glutamatergic system (iGluRs, mGluRs, EAATs) after neonatal febrile seizures.

The most severe and persistent molecular alterations occur in the ventral hippocampus and medial prefrontal cortex, key nodes for emotional regulation and cognition.

The behavioral outcome is characterized by a hyperanxious phenotype with locomotor and habituation deficits, but with working memory and sociability remaining unaffected.

The findings reveal a precise neurobiological mechanism that could underlie the increased risk of anxiety-related disorders following early-life febrile seizures.

Febrile seizures (FS) are a common childhood neurological event associated with an increased risk of long-term cognitive and emotional deficits, though the precise mechanisms remain elusive. Using a rat model, we investigated the long-term effects of FS induced on postnatal day 10, assessing outcomes in young adulthood (P45-55). We report region-specific neuronal loss in the hippocampus, more extensive in the ventral segment. Molecular analysis revealed a broad downregulation of genes encoding ionotropic and metabotropic glutamate receptors and excitatory amino acid transporters. These alterations were most severe and persistent in the ventral hippocampus and medial prefrontal cortex. Behaviorally, rats with neonatal FS exhibited a hyperanxious phenotype, characterized by reduced locomotor and exploratory activity and impaired habituation to a novel environment. In contrast, spatial working memory and social behavior remained intact. Our results provide the first comprehensive evidence that neonatal FS trigger long-term, region-specific disruptions of the glutamatergic system within hippocampal–prefrontal circuits. These findings identify vulnerable molecular targets and precise neurobiological mechanisms that may underlie the heightened risk of anxiety-related disorders following early-life FS, suggesting new avenues for therapeutic intervention.