Spatial memory impairments in a prediabetic rat model.
Neuroscience. 2013-10-01; 250: 565-577
DOI: 10.1016/j.neuroscience.2013.07.055
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Diabetes is associated with an increased risk for brain disorders, namely
cognitive impairments associated with hippocampal dysfunction underlying diabetic
encephalopathy. However, the impact of a prediabetic state on cognitive function
is unknown. Therefore, we now investigated whether spatial learning and memory
deficits and the underlying hippocampal dysfunction were already present in a
prediabetic animal model. Adult Wistar rats drinking high-sucrose (HSu) diet (35%
sucrose solution during 9 weeks) were compared to controls’ drinking water. HSu
rats exhibited fasting normoglycemia accompanied by hyperinsulinemia and
hypertriglyceridemia in the fed state, and insulin resistance with impaired
glucose tolerance confirming them as a prediabetic rodent model. HSu rats
displayed a poorer performance in hippocampal-dependent short- and long-term
spatial memory performance, assessed with the modified Y-maze and Morris water
maze tasks, respectively; this was accompanied by a reduction of insulin
receptor-β density with normal levels of insulin receptor substrate-1
pSer636/639, and decreased hippocampal glucocorticoid receptor levels without
changes of the plasma corticosterone levels. Importantly, HSu animals exhibited
increased hippocampal levels of AMPA and NMDA receptor subunits GluA1 and GLUN1,
respectively, whereas the levels of protein markers related to nerve terminals
(synaptophysin) and oxidative stress/inflammation (HNE, RAGE, TNF-α) remained
unaltered. These findings indicate that 9 weeks of sucrose consumption resulted
in a metabolic condition suggestive of a prediabetic state, which translated into
short- and long-term spatial memory deficits accompanied by alterations in
hippocampal glutamatergic neurotransmission and abnormal glucocorticoid
signaling.