Changes in Synaptic Plasticity and Glutamate Receptors in Type 2 Diabetic KK-Ay Mice

Abstract

In the present study, the progressive alteration of cognition and the mechanisms of reduction in long-term potentiation (LTP) in spontaneous obese KK-Ay type 2 diabetic mice were investigated. In the study, 3-, 5-, and 7-month-old KK-Ay mice were used. The results indicated that KK-Ay mice showed cognitive deficits in the Morris water maze test beginning at the age of 3 months. LTP was significantly impaired in KK-Ay mice during whole study period (3 to 7 months). The above deficits were reversible at an early stage (3 to 5 months old) by diet intervention. Moreover, we found the underlying mechanisms of LTP impairment in KK-Ay mice might be attributed to abnormal phosphorylation or expression of postsynaptic glutamate receptor subunits instead of alteration of basal synaptic transmission. The expression levels of NR1, NR2A, and NR2B subunits of N-methyl-d-aspartate receptors (NMDARs) were unchanged while the Tyr-dependent phosphorylation of both NR2A and NR2B subunits were significantly reduced in KK-Ay mice. The level of p-Src expression mediating this process was decreased, and the level of αCaMKII autophosphorylation was also reduced. Meanwhile, the GluR1 of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) was decreased, and GluR2 was significantly increased. These data suggest that deficits in synaptic plasticity in KK-Ay mice may arise from the abnormal phosphorylation of the NR2 subunits and the alteration of subunit composition of AMPARs. Diet intervention at an early stage of diabetes might alleviate the cognitive deficits and LTP reduction in KK-Ay mice.

Studies of pathology and pharmacology of diabetic encephalopathy with KK‐Ay mouse model

“…Our study demonstrated that KK‐Ay mouse is a stable and useful model of T2DM and the mice showed obviously cognitive deficiency in Morris water maze test. It was similar to the previous studies, which KK‐Ay mice displayed a cognitive dysfunction at quite young with low activity of long‐term potentiation (LTP) . However, diabetes‐induced dementia is different from AD in pathogenesis.…”

“…Our previous study had shown that the body weight, random blood glucose, cholesterol, triglyceride, and insulin of KK‐Ay mice were significantly increased compared to control age‐matched group at 3,5, and 7 months of age, which suggested that KK‐Ay is a reliable model of T2DM . Furthermore, KK‐Ay mice showed obvious spatial learning and memory deficits in the diabetic duration .…”

“…So far, the study of obese diabetes inducing cognitive deficits was scarcely reported in KK‐Ay mice. In our previous study, we had found a high incidence of dementia in KK‐Ay mice …”

“…In our previous study, we had found a high incidence of dementia in KK-Ay mice. 16 In the present study, we simultaneously observed the histological and functional change in both neuron and glia in the hippocampus of 3-, 5-, and 7-month-old KK-Ay mice to elucidate the mechanism of DE in the duration of the disease. In addition, we investigated the protective effects of two agents on DE, one is donepezil which is a classical agent for AD and another is dl-PHPB (potassium 2-(1-hydroxypentyl)-benzoate) which is a novel drug candidate for the treatment of cerebral ischemic stroke.…”

“…Our previous study had shown that the body weight, random blood glucose, cholesterol, triglyceride, and insulin of KK-Ay mice were significantly increased compared to control age-matched group at 3,5, and 7 months of age, which suggested that KK-Ay is a reliable model of T2DM. 16 Furthermore, KK-Ay mice showed obvious spatial learning and memory deficits in the diabetic duration. 16 In the present study, we found that PHPB (150 mg/kg) and donepezil (3 mg/kg) treatment had no significant effect on the biochemistry index of 5-month-old KK-Ay mice but DR could reduce the blood glucose and body weight ( Figure 1A-D).…”