Role of GABAA receptors in EEG activity and spatial recognition memory in aged APP and PS1 double transgenic mice

Abstract

Alzheimer's disease (AD) is a leading cause of dementia, with no effective treatment currently available. However, targeting the aging mechanism may improve outcomes and γ-aminobutyric acid (GABA) system alteration could have implications for treatment of cognitive decline in old age. We studied the effects of the GABA system on brain activity in aged APP and PS1 transgenic mice. Low dose (0.1 mg/kg i.p.) GABA_A agonist muscimol and antagonist bicuculline were administered for moderate system activation and inhibition, respectively. EEGs from the hippocampus (Hip) and prefrontal cortex (PFC) were recorded under spontaneous state and during Y-maze performance. Basally, AD mice exhibited increased spontaneous EEG delta (2-4 Hz) and decreased spontaneous EEG alpha (8-12 Hz) activity in the Hip, and decreased Y-maze EEG theta (4-8 Hz) activity in the PFC. Interestingly, GABA_A activation and inhibition in AD mice reduced EEG delta activity and increased EEG theta activity in the PFC, and behaviorally improved spatial recognition memory during Y-maze testing. Decreased spontaneous EEG delta activity was also observed in the PFC. Specifically, GABA_A activation primarily affected low frequency EEG (2-12 Hz) activity in the PFC, whereas inhibition affected EEG activity across many frequencies in the PFC and Hip. These data provide evidence for slower brain activity in AD mice. Importantly, improved spatial memory after GABA_A activation and inhibition may be explained by brain rhythm recovery in certain regions. Our study highlights the potential clinical use of GABA_A drugs to improve cognitive disorders and restore neural network activity in AD.

Keywords: Alzheimer's disease; Bicuculline; Hippocampus; Muscimol; Prefrontal cortex; Spatial memory.