Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer's disease

Abstract

Type 2 diabetes has been identified as a risk factor for Alzheimer disease (AD). Insulin signalling is often impaired in AD, contributing to the neurodegeneration seen in AD. Previous studies have shown that the incretin glucagon-like peptide 1 (GLP-1) helps to normalise insulin signalling in type 2 diabetes. GLP-1 also plays important roles in neuronal activity and brain functions. We tested the specific role of GLP-1 receptors in synaptic plasticity and cognitive processes in a GLP-1 receptor knockout (Glp1r(-/-)) mouse model. In an open field assessment, no general difference in exploratory and anxiety was found except for a small decrease in running speed was found (p<0.05). In an object recognition task, Glp1r(-/-) mice explored objects in a similar way to WT controls but did not learn to differentiate between novel and familiar objects (p<0.05) while in an object relocation task, no impairment was observed. In a water maze task, Glp1r(-/-) mice were impaired in the acquisition phase (p<0.001), and also in the probe recall task (p<0.05). LTP in area CA1 of the hippocampus was severely impaired in Glp1r(-/-) mice (p<0.0001). Paired-pulse facilitation was also impaired at 25ms interstimulus interval (p<0.05) but not at longer intervals. The results demonstrate that the murine GLP-1R plays an important role in the control of synaptic plasticity and in some forms of memory formation. The results shed light on the molecular processes that underlie the neuroprotective properties of GLP-1 analogues in animal models of Alzheimer's disease.