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The entorhinal cortex (EC) is one of the earliest affected brain regions in Alzheimer’s disease (AD). EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG) with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were investigated. The amyloid beta (Aβ) 1–42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin) accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days), almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer’s disease.

AbstractThe hippocampus exhibits a wide range of epilepsy-related abnormalities and is situated in the mesial temporal lobe, where limbic seizures begin. These abnormalities could affect membrane excitability and lead to overstimulation of neurons. Multiple overlapping processes refer to neural homeostatic responses develop in neurons that work together to restore neuronal firing rates to control levels. Nevertheless, homeostatic mechanisms are unable to restore normal neuronal excitability, and the epileptic hippocampus becomes hyperexcitable or hypoexcitable. Studies show that there is hyperexcitability even before starting recurrent spontaneous seizures, suggesting although hippocampal hyperexcitability may contribute to epileptogenesis, it alone is insufficient to produce epileptic seizures. This supports the concept that the hippocampus is not the only substrate for limbic seizure onset, and a broader hyperexcitable limbic structure may contribute to temporal lobe epilepsy (TLE) seizures. Nevertheless, seizures also occur in conditions where the hippocampus shows a hypoexcitable phenotype. Since TLE seizures most often originate in the hippocampus, it could therefore be assumed that both hippocampal hypoexcitability and hyperexcitability are undesirable states that make the epileptic hippocampal network less stable and may, under certain conditions, trigger seizures.

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