Decreased GABA Receptor Binding in the Cerebral Cortex of Insulin Induced Hypoglycemic and Streptozotocin Induced Diabetic Rats

Abstract

Hypoglycemia is the major problem to blood glucose homeostasis in treatment of diabetes and is associated with severe irreversible consequences including seizures, coma and death. GABAergic inhibitory function in the cerebral cortex plays an important role in controlling the excitability and responsiveness of cortical neurons. Present study analysed effects of insulin induced hypoglycemia and streptozotocin induced diabetes on the cortical GABA receptor binding, GABA(Aά1), GABA(B) receptor subtype expression, GAD and GLUT3 expression. Diabetic rats showed decreased [(3)H] GABA binding in the cerebral cortex compared to control while hypoglycemia exacerbated the decrease. GABA receptor subunits; GABA(Aά1), GABA(B) and GAD expression significantly decreased in diabetic rats whereas hypoglycemia significanly decreased the expression compared to diabetic. GLUT3 expression significantly up regulated during both hypo and hyperglycemia. Our results showed that hypoglycemia and hyperglycemia decreased GABAergic neuroprotective function in the cerebral cortex, which account for the increased vulnerability of cerebral cortex to subsequent neuronal damage during hypo/hyperglycemia.

Hormonal Signaling Systems of the Brain in Diabetes Mellitus

“…This is the evidence that hypoglycemia amplifies the adverse effects of hyperglycemia on GABAergic system, and the impairments of functions of GABAergic neurons in the diabetic cerebral cortex are intensified in hypoglycemia. The expression of glutamate decarboxylase, the rate-limiting enzyme of GABA synthesis, which is used as a marker of GABAergic activity, was also significantly down regulated in DM and hypoglycemia exacerbated the altered expression (Antony et al, 2010a). The same picture is found in the cerebellum, where GABA receptors are involved in control of coordination and motor learning and, like in the cerebral cortex, play a critical role in neuronal excitability and modulation of synaptic neurotransmission (Luján, 2007).…”

“…The various neurotransmitter systems, including dopaminergic, serotonergic, cholinergic, glutamatergic, and GABAergic, undergo a significant change in DM (Jackson & Paulose, 1999;Gireesh et al, 2008;Antony et al, 2010a;Anu et al, 2010; T.P. Kumar et al, 2010) (Fig.…”

“…The inhibitory GABA-releasing interneurons mediate the function of excitatory glutamatergic neurons in the brain regions, which contributes significantly to the control of glutamate content in brain regions and prevents glutamate toxicity induced in the brain of hypo-and hyperglycemic diabetic rats. Disruption of GABAergic inhibition induces seizures leading to neuronal damage and, therefore, the pathophysiology of many seizure disorders is the result of alteration of GABA receptor function (Antony et al, 2010a). It was shown that the synaptic level of GABA and its release in the diabetic brain are slightly changed or remain unchanged.…”

Blockade of corticosteroid receptors induces anxiolytic-like effects in streptozotocin-induced diabetic mice, and synergizes with diazepam

“…Thus, some studies showed increases in extracellular GABA concentrations (Ohtani et al, 1997;Chan et al, 2011), whereas others did not (Guyot et al, 2001). Moreover, it has been reported that in control rats but not in diabetic animals, GABA levels are increased after stress (Gomez et al, 2003), whereas the number of GABA receptors is decreased (Antony et al,. 2010;Sherin et al,.…”

Independent and symmetric seizures from parasagittal cortex: Is this a feature of profound hypoglycemia?

“…To explain the selective vulnerability of the corpus callosum, and specifically, the subgroups of callosal projection neurons, experimental studies suggest the combined role of excitotoxicity as well as glucose starvation in the pathogenesis of hypoglycemic brain injury [11]. For example, in rat models, hypoglycemia decreases GABAergic neuroprotective function and increased vulnerability of the cerebral cortex to neuronal damage [12]. Cortical projection neurons have discrete intrinsic membrane properties, bursting behavior, and spontaneous spike frequencies as compared to other cortical neurons.…”