Long-Term Hyperglycemia Causes Depressive Behaviors in Mice with Hypoactive Glutamatergic Activity in the Medial Prefrontal Cortex, Which Is Not Reversed by Insulin Treatment

Abstract

The etiology of hyperglycemic-induced depressive behaviors is unclear. We hypothesized that long-term hyperglycemia may induce long-lasting disturbances in glutamatergic signaling and neural damages, causing depressive behaviors. To prove our hypothesis, a C57BL/6N mouse model of hyperglycemia was maintained for 4 weeks (equivalent to approximately 3 years in humans), after which insulin treatment was administered for an additional 4 weeks to normalize hyperglycemia-induced changes. Hyperglycemic mice showed depressive-like behaviors. Glutamatergic neurons and glial cells in the medial prefrontal cortex (mPFC) were affected by hyperglycemia. Insulin treatment improved blood glucose, water intake, and food intake to normoglycemic levels, but did not improve depressive-like behaviors. Glutamatergic signaling decreased with long-term hyperglycemia and did not normalize with insulin-induced normoglycemia. Importantly, hyperglycemia-induced changes in the mPFC were almost not reversed by the 4-week insulin treatment. In particular, levels of insulin receptor beta subunit (IRβ), IRS-1, vesicular glutamate transporter 1, glutamine transporter SNAT2, phosphate-activated glutaminase, and GLUT-3 were not changed by insulin. Nitration and the dephosphorylation of IRβ in the PFC also did not improve with insulin treatment. Therefore, our results suggest that hypoactive glutamatergic activity in the mPFC is involved in diabetic-associated depressive behaviors, and it is difficult to cure with glycemic regulation alone.

Therapeutic potential of enzymatically extracted eumelanin from squid ink in type 2 diabetes mellitus ICR mice: Multifaceted intervention against hyperglycemia, oxidative stress and depression

“…Baek et al . reported that hyperglycemia exerts an impact on glutamatergic neurons and glial cells located within the medial prefrontal cortex of mice, leading to the manifestation of depressive‐like behavior 47 . Our own experimental findings are consistent with these observations.…”

“…Baek et al reported that hyperglycemia exerts an impact on glutamatergic neurons and glial cells located within the medial prefrontal cortex of mice, leading to the manifestation of depressive-like behavior. 47 Our own experimental findings are consistent with these observations. In the tail-hanging experiment, mice exposed to ANF-40 demonstrated heightened energy levels, stronger physical force, and shorter immobilization times.…”

Daily fluctuations in blood glucose with normal aging are inversely related to hippocampal synaptic mitochondrial proteins

“…One study uncovered a very modest reduction in GLUT3 mRNA from the frontal cortex of 10 weeks-old db/db mice, but more advanced aging was not studied [79] . Using the STZ diabetic model, significant reductions in GLUT3 mRNA and protein are induced throughout cortex and hippocampus and, further, recovered in an insulin dependent manner [80] , [81] . While STZ robustly increases blood glucose, the induced loss of insulin producing cells is phenotypically similar to Type I diabetes, and not Type II diabetes that is prevalent in aging or with obesity.…”

The Role of Glutamine Homeostasis in Emotional and Cognitive Functions

“…Decreased glutamatergic activity has been commonly found in various animal models with emotional and cognitive disorders, including the L-AAA/MSO/MeAIB-treated mice described above [20,31]; chronic stress-induced depression and cognitive-impairment models [20,29]; a long-term hyperglycemia-induced social interaction disorder and depression model [88]; bis(2-ethylhexyl) phthalate (DEHP)-induced depression, learning and memory impairment, and social interaction deficit models [63,64]; a mouse model of spatial memory impairment induced by MSO treatment during synaptic development [22]; and a triple-transgenic (3xTg)-AD mouse model [32] (Figure 1). As hypoactive glutamatergic neurotransmission of various causes is commonly observed in different animal models, the maintenance of glutamatergic neurotransmission has emerged as an important strategy for developing new preventive and therapeutic agents against emotional and cognitive disorders.…”