Is there a role for GABA-A receptor alpha-5 subunits in cognitive deficits caused by consumption of a high fat diet?

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This project will use dietary manipulations in mice and look at behavioural effects on memory alongside electrophysiological changes in synaptic plasticity and changes in receptor expression in the brain. It will investigate the question of whether GABA-A receptor alpha-5 subunits, a target for cognitive enhancing drugs, are upregulated by a high fat diet and whether this is linked to inflammatory cytokine activation. It aims to define a mechanistic link between fat consumption and memory loss. Cognitive deficits in mice appear within days of initiating high fat feeding. This models cognitive decline seen in Type II diabetics and in fact in healthy young subjects with a high BMI (1). We have previously demonstrated that a high-fat diet (HFD), in mice, rapidly and dramatically impacts on complex associative episodic-like memory, which incorporates information about specific events, including spatial locations and the contextual features of the environment in which the event took place (2). Episodic memory is one of the memories initially compromised in Alzheimer's disease and is located in the hippocampus. These cognitive deficits could be caused by the activation of inflammatory cytokines such as the interleukins, which are thought to modulate GABA-A receptor function (3). GABA-A receptors containing the alpha-5 subunit are found in a high density in the hippocampus and are involved in learning and memory. Downregulating these receptors can be a method of cognitive enhancement which has been shown in healthy human volunteers and is currently in clinical trials for Down's syndrome. Could these receptors could be a link between high fat feeding and cognitive decline, potentially due to their activation by inflammatory cytokines?