Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Cochin 682 022, Kerala, India.
Neuroscience. 2012 Jan 27;202:69-76. doi: 10.1016/j.neuroscience.2011.11.058. Epub 2011 Dec 3.
Neurotransmitter receptor functional regulation plays an important role in controlling the excitability and responsiveness of hippocampal neurons. Deregulation of its function is associated with seizure generation, motor deficits, and memory impairment. In the present study we investigated the changes in hippocampal cholinergic and GABA receptor binding and gene expression in insulin-induced hypoglycemic and streptozotocin-induced diabetic rats. Expression of cholinergic enzymes; acetylcholine esterase (AChE) and choline acetyltransferase (ChAT) upregulated and downregulated, respectively, in diabetic group, which was further exacerbated by hypoglycemia. Total muscarinic receptor, muscarinic M1, and GABA maximal binding (B(max)) significantly decreased in hypoglycemic and diabetic rats. In hypoglycemic group, the B(max) showed further decline compared with diabetes. Muscarinic M3 receptor B(max) and gene expression upregulated in hypoglycemic and diabetic group. Alpha7 nicotinic acetylcholine receptor (α7 nAChR) expression significantly downregulated in hypoglycemic and diabetic rats. Gene expression of glutamate decarboxylase (GAD), GABAAα1, and GABAB in hypoglycemic and diabetic rats downregulated, with more significant decrease in hypoglycemic group. Present findings show altered cholinergic, muscarinic, nicotinic receptor expression and thereby function. Decreased GABA receptor expression is associated with decline in GABAergic neurotransmission. Thus cholinergic receptor dysfunction and decreased GABAergic neuroprotective inhibitory function in the hippocampus of hypoglycemic and diabetic rats account for the increased vulnerability of hippocampus predisposing to neuronal damage, which is suggested to contribute to cognitive impairment and memory deficit reported in hypoglycemia and diabetes. Also, recurrent hypoglycemia in diabetes exacerbates the hippocampal dysfunction induced by diabetes, which has clinical significance in diabetes therapy.
神经递质受体功能调节在控制海马神经元的兴奋性和反应性方面起着重要作用。其功能失调与癫痫发作、运动缺陷和记忆障碍有关。在本研究中，我们研究了胰岛素诱导的低血糖和链脲佐菌素诱导的糖尿病大鼠中海马胆碱能和 GABA 受体结合和基因表达的变化。胆碱能酶的表达；乙酰胆碱酯酶（AChE）和胆碱乙酰转移酶（ChAT）分别上调和下调，在糖尿病组中进一步加剧，低血糖进一步恶化。总毒蕈碱受体、毒蕈碱 M1 和 GABA 最大结合（B(max))在低血糖和糖尿病大鼠中显著降低。在低血糖组中，B(max)与糖尿病相比进一步下降。低血糖和糖尿病组中毒蕈碱 M3 受体 B(max)和基因表达上调。α7 烟碱型乙酰胆碱受体（α7 nAChR）在低血糖和糖尿病大鼠中的表达显著下调。低血糖和糖尿病大鼠中谷氨酸脱羧酶（GAD）、GABAAα1 和 GABAB 的基因表达下调，低血糖组下降更明显。目前的研究结果表明，胆碱能、毒蕈碱、烟碱受体的表达和功能发生改变。GABA 受体表达的降低与 GABA 能神经传递的下降有关。因此，低血糖和糖尿病大鼠海马中的胆碱能受体功能障碍和 GABA 能神经保护抑制功能的降低导致海马易损性增加，这可能导致低血糖和糖尿病中报道的认知障碍和记忆缺陷。此外，糖尿病中反复发生的低血糖会加剧糖尿病引起的海马功能障碍，这在糖尿病治疗中具有临床意义。
