NMDA receptor subunits are modified transcriptionally and post-translationally in the brain of streptozotocin-diabetic rats

Abstract

Diabetes mellitus is known to be associated with neurological complications in both the peripheral and the central nervous system. Manifestations of cerebral disorders in diabetic patients include alterations in neurotransmission, electrophysiological abnormalities, structural changes and cognitive deficits [1±4]. In animal models of diabetic pathology, such as the streptozotocin-diabetic rat, spatial learning impairments have been reported [5]. This cognitive deficit is associated with changes in hippocampal synaptic plasticity, including an impaired expression of long term potentiation (LTP) [5,6] and enhanced expres- Diabetologia (1999) Abstract Aims/hypothesis. Moderate disturbances of learning and memory were recognized as a complication of diabetes mellitus in patients. The streptozotocin-diabetic rat, an animal model of insulin-dependent diabetes, shows impairments in spatial memory and in long-term potentiation expression. We have studied the effect of experimental diabetes on expression of post-synaptic glutamate N-Methyl-D-Aspartate ionotropic receptors and of other key proteins regulating synaptic transmission at the post-synaptic compartment. Methods. In situ hybridization and Western blot analysis were used to assess expression and protein concentration of N-Methyl-D-Aspartate receptors and a-calcium-calmodulin-dependent kinase II. Receptor subunits aCaMKII-dependent phosphorylation was studied in post-synaptic densities obtained from the hippocampus and cortex of control, streptozotocindiabetic and insulin-treated rats. Results. The transcript levels of NR1 and NR2A subunits of N-Methyl-D-Aspartate were unchanged in rats with a diabetic duration of 3 months when compared with age-matched control rats. Accordingly, NR1 and NR2A as well as GluR1, GluR2/3, PSD-95 and aCaMKII protein concentrations in post-synaptic densities were the same in both control and diabetic rats, whereas the immunoreactivity for NR2B was reduced by about 40 %. In addition, the activity of aCaMKII on exogenous substrates, such as syntide-2, and the phosphorylation of NR2A/B subunits of N-Methyl-D-Aspartate receptor was reduced in hippocampal post-synaptic densities of streptozotocin-diabetic rats as compared with control rats. Furthermore, we show that insulin intervention for 3 months after diabetic duration partially restored both aCaMKII activity and NR2B levels. Conclusion/interpretation. N-Methyl-D-Aspartate receptor expression and phosphorylation is possibly involved in behavioural and electrophysiological abnormalities observed in streptozotocin-diabetic rats. [Diabetologia (1999) 42: 693±701]

Diabetes changes ionotropic glutamate receptor subunit expression level in the human retina

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Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

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