Glucose is the sole neural fuel for the brain, and is essential for cognitive function. It has been argued that abnormalities in glucose tolerance are associated with impairments in cognitive function. Experimental obese model mice have been obtained by the i.p. injection of monosodium glutamate (MSG; 2 mg/g) once a day for 5 days from one day after the birth. MSG-treated mice developed glucose intolerance and exhibited chronic neuroendocrine dysfunction associated with the marked cognitive malfunction at 28-29 weeks of age. Although hippocampal synaptic plasticity was impaired in MSG-treaded mice, changes in synaptic transmission remain unknown. In the present study, we examined whether glucose intolerance influenced cognitive function, synaptic properties, and protein expression in the hippocampus. We demonstrated that MSG-treated mice developed glucose intolerance due to impaired effectiveness of insulin action, and showed cognitive malfunction in the Y-maze test. Moreover, excitatory synaptic transmission at Schaffer collateral-CA1 pyramidal (SC-CA1) synapses in hippocampal slices was affected in MSG-treated mice, compared with age-matched control mice. Protein levels of vesicular glutamate transporter 1 (VGLUT1) and GluR1 glutamate receptor subunits decreased in the CA1 region of MSG-treated mice. These results suggest that deficits in glutamatergic presynapse as well as postsynapse lead to impaired synaptic plasticity in MSG-treated mice during the development of glucose intolerance. It might be important to examine changes in glucose tolerance for preventing the cognitive malfunction associated with diabetes.