Enhanced HCN-Dependent Regulation of Temporoammonic Integration and Entorhinal-Hippocampal Epileptiform Coupling Following Febrile Seizures.

Mechanisms linking early-life developmental pathologies, such as cortical malformations and febrile seizures (FS), to persistent hippocampal circuit alterations remain incompletely understood. We investigated intrinsic excitability, HCN channel function, pathway-specific synaptic integration, and entorhinal-hippocampal network activity using rat models of focal freeze lesion (FFL) at postnatal day (P) 0, experimental FS at P10, and their combination (FFL + FS). Whole-cell recordings at P21-23 showed that FFL predominantly reduced CA1 neuronal excitability, whereas the FS condition was associated with increased hyperpolarization-activated cation current (Ih) amplitude and sag ratio. This functional HCN enhancement was not accompanied by detectable changes in bulk hippocampal Hcn1 or Hcn2 mRNA levels and remained evident in FFL + FS animals. HCN blockade enhanced synaptic summation in both Schaffer collateral and temporoammonic pathways, with a greater relative effect on temporoammonic inputs after FS. In the 4-aminopyridine model of induced epileptiform activity, HCN blockade increased hippocampal event burden and strengthened EC-leading temporal coupling with CA1, with particularly pronounced effects following FS. Together, these findings suggest that persistent HCN enhancement following prolonged experimental FS is associated with greater HCN-dependent regulation of temporoammonic integration and entorhinal-hippocampal coupling under 4-AP-induced epileptiform conditions.