Abstract
ObjectiveDiabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. To elucidate the specific role of brain insulin signalling in neuronal functions that are relevant for cognitive processes we have investigated the behaviour of neurons and synaptic plasticity in the hippocampus of mice lacking the insulin receptor substrate protein 2 (IRS-2).Research Design and MethodsTo study neuronal function and synaptic plasticity in the absence of confounding factors such as hyperglycaemia, we used a mouse model with a central nervous system- (CNS)-restricted deletion of IRS-2 (NesCreIrs2KO).ResultsWe report a deficit in NMDA receptor-dependent synaptic plasticity in the hippocampus of NesCreIrs2KO mice, with a concomitant loss of metaplasticity, the modulation of synaptic plasticity by the previous activity of a synapse. These plasticity changes are associated with reduced basal phosphorylation of the NMDA receptor subunit NR1 and of downstream targets of the PI3K pathway, the protein kinases Akt and GSK-3β.ConclusionsThese findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling.
Highlights
Substantial epidemiological evidence supports an association between diabetes mellitus and cognitive impairment [1,2,3]
We report a deficit in NMDA receptor-dependent synaptic plasticity in the hippocampus of NesCreIrs2KO mice, with a concomitant loss of metaplasticity, the modulation of synaptic plasticity by the previous activity of a synapse
Whole-cell recordings revealed no significant differences in the resting membrane potential (Fig. 1A) and membrane resistance (Fig. 1B) of CA1 pyramidal neurons from NesCreIrs2KO mice and littermate controls
Summary
Substantial epidemiological evidence supports an association between diabetes mellitus and cognitive impairment [1,2,3]. Animal models of diabetes exhibit impaired learning and memory [4,5,6,7,8], effectively prevented by administration of insulin [4,6]. Diabetic rodent models and human patients are susceptible to suffer complex effects of systemic hyperglycaemia and glucose intolerance, such as vascular disorders, hypertension and heart disease, which can independently exacerbate cognitive impairment [1]. This makes it difficult to dissect the potential role of brain insulin signalling in cognition and its cellular and molecular mechanisms
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