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

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.