Riluzole ameliorates soluble Aβ1–42-induced impairments in spatial memory by modulating the glutamatergic/GABAergic balance in the dentate gyrus

Abstract

Soluble amyloid beta (Aβ) is believed to contribute to cognitive deficits in the early stages of Alzheimer's disease (AD). Increased soluble Aβ1–42 in the hippocampus is closely correlated with spatial learning and memory deficits in AD. Riluzole (RLZ), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), has beneficial effects for AD. However, the mechanism underlying the effects remains unclear. In this study, its neuroprotective effect against soluble Aβ1–42-induced spatial cognitive deficits in rats was assessed. We found that intrahippocampal injection of soluble Aβ1–42 impaired spatial cognitive function and suppressed long-term potentiation (LTP) of the DG region, which was relevant to soluble Aβ1–42-induced shift of the hippocampal excitation/inhibition balance toward excitation. Interestingly, RLZ ameliorated Aβ1–42-induced behavioral and LTP impairments through rescuing the soluble Aβ1–42-induced excitation/inhibition imbalance. RLZ attenuated Aβ1–42-mediated facilitation of excitatory synaptic transmission by facilitating glutamate reuptake and decreasing presynaptic glutamate release. Meanwhile, RLZ attenuated the suppression of inhibitory synaptic transmission caused by Aβ1–42 by potentiating postsynaptic GABA receptor function. These results suggest that RLZ exerts a neuroprotective effect against soluble Aβ1–42-related spatial cognitive deficits through rescuing the excitation/inhibition imbalance, and it could be a potential therapy for AD.