Persistent sodium currents contribute to Aβ1-42-induced hyperexcitation of hippocampal CA1 pyramidal neurons

Abstract

Patients with Alzheimer's disease (AD) have elevated incidence of epilepsy. Moreover, neuronal hyperexcitation occurs in transgenic mouse models overexpressing amyloid precursor protein and its pathogenic product, amyloid β protein (Aβ). However, the cellular mechanisms of how Aβ causes neuronal hyperexcitation are largely unknown. We hypothesize that the persistent sodium current (INaP), a subthreshold sodium current that can increase neuronal excitability, may in part account for the Aβ-induced neuronal hyperexcitation. The present study was designed to evaluate the involvement of INaP in Aβ-induced hyperexcitation of hippocampal CA1 pyramidal neurons using a whole-cell patch-clamp recording technique. Our results showed that bath application of soluble Aβ1-42 increased neuronal excitability in a concentration-dependent manner. Soluble Aβ1-42 also increased the amplitude of INaP without significantly affecting its activation properties. In the presence of riluzole (RLZ), an antagonist of INaP, the Aβ1-42-induced neuronal hyperexcitation and INaP augmentation were significantly inhibited. These findings suggest that soluble Aβ1-42 may induce neuronal hyperexcitation by increasing the amplitude of INaP and that RLZ can inhibit the Aβ1-42-induced abnormal neuronal activity.

Keywords: Alzheimer's disease; Amyloid β; Hyperexcitation; Persistent sodium current; Riluzole.