Diabetes mellitus (DM) is known to be a risk factor in the development of deficits in cognition, learning, and memory. In DM animal models, including the streptozotocin (STZ)-induced diabetic rodent model, abnormalities in the regulation of several neurotransmitters have been reported. However, the role in DM of d-serine, an endogenous co-agonist of glutamatergic N-methyl-d-aspartate receptors, remains unknown. Here, we measured the amounts of d-/l-serine and l-glutamate in the hippocampi of STZ-treated mice using a 2D-HPLC system from acute to chronic phases after the induction of DM. STZ treatment significantly increased the d-serine level by 23.7% in the hippocampus compared with vehicle treatment at 1 week after the injection, whereas it did not affect the levels of l-serine. In contrast, l-glutamate levels in the hippocampus were elevated at 3 days after STZ injection and rather decreased at 1 week after that. Such alterations in the amino acids were not evident in the chronic phases. We further tested whether the STZ-induced d-serine increase was caused by DM pathophysiology. In vivo, subcutaneous insulin implants into STZ-treated mice restored the elevated d-serine levels in the hippocampus. An in vitro study using primary cultured hippocampal neurons revealed that treatments of STZ did not directly affect the level of d-serine secreted in the cultured media. These results indicate that DM pathology caused by insulin deficiency triggers transient d-serine increase and l-glutamate alteration in the hippocampus. Such aberrant regulations of excitatory neurotransmitters may be relevant to the formation of DM-related dysfunction of the central nervous system (CNS).
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