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

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 (I_h) 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.