Histological and neurochemical effects of fetal treatment with methylazoxymethanol on rat neocortex in adulthood
Histological and neurochemical effects of fetal treatment with methylazoxymethanol on rat neocortex in adulthood
复制标题
甲基偶氮甲醇胎儿治疗对成年大鼠新皮质的组织学和神经化学影响
DOI：
10.1016/0006-8993(79)90946-6
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发表时间：
1979
期刊：
影响因子：
2.9
通讯作者：
J. Coyle
中科院分区：
文献类型：
--
作者：
M. Johnston;J. Coyle
发育中的大鼠在妊娠15天暴露于甲基甲氧基甲醇醋酸酯（MAM）可导致前脑小脑畸形。这种有效的烷基化剂对分裂细胞具有选择性的细胞毒性。由于不同的神经元群体在新皮质在妊娠期间有丝分裂活动的时间变化很大，预测一些组将不同地减少治疗。经治疗的大鼠成年后的新皮质的组织学检查显示II-IV层的主要损失，较深的层相对保存。萎缩的成人新皮层进一步表征了几个定义的突触前和突触后神经化学标志物的测定。GABA能神经元的总标记物显著降低（谷氨酸脱羧酶-71%，[3H]GABA突触体摄取-63%，内源性GABA -59%）。与皮质膜结合的总[3H]GABA减少67%。总[3H]谷氨酸突触体摄取和内源性谷氨酸分别减少71%和65%。相比之下，去甲肾上腺素神经支配的突触前总标记物几乎没有改变，但酪氨酸羟化酶、[3H]去甲肾上腺素突触体摄取和内源性去甲肾上腺素的浓度分别增加了275%、130%和133%。萎缩皮质中胆碱能突触前标记物的浓度（胆碱乙酰转移酶+97%，内源性乙酰胆碱+64%）也增加，但程度低于去甲肾上腺素能神经支配。毒蕈碱类胆碱能拮抗剂[3H]喹啉苄基苯甲酸酯和β-肾上腺素能受体拮抗剂[3H]二氢阿普萘洛尔的特异性结合分别降低25%和29%。因此，在15 DG时，MAM治疗严重减少了包括gaba能和谷氨酸能神经元在内的内在神经元群，并产生相对由去甲肾上腺素能和胆碱能神经元过度支配的皮质萎缩。mam诱导的微脑畸形是一个有用的模型系统，用于产生相对选择性的远端脑神经元病变，以及研究发育性脑损伤后神经化学关系的改变。
Forebrain microencephaly results when developing rats are exposed to methylazoxymethanol acetate (MAM) at 15 days of gestation (DG). This potent alkylating agent is selectively cytotoxic for dividing cells. Since distinct neuronal populations in neocortex vary greatly with respect to timing of mitotic activity during gestation, it was predicted that some groups would be differentially reduced by treatment. Histological examination of neocortex from treated rats grown to adulthood revealed major losses of laminae II–IV with relative preservation of deeper layers. The atrophic adult neocortex was further characterized by assay of several defined pre- and postsynaptic neurochemical markers. Total markers for GABAergic neurons were greatly reduced (glutamate decarboxylase —71%, [3H]GABA synaptosomal uptake —63% and endogenous GABA —59%). Total [3H]GABA binding to cortical membranes was reduced 67%. Total [3H]glutamate synaptosomal uptake and endogenous glutamate were reduced 71% and 65% respectively. In contrast, total presynaptic markers for noradrenergic innervation were minimally altered but concentration of tyrosine hydroxylase, [3H]norepinephrine synaptosomal uptake and endogenous norepinephrine were increased by 275%, 130% and 133%, respectively. Concentration of cholinergic presynaptic markers was also increased (choline acetyltransferase +97%, endogenous acetylcholine +64%) in atrophic cortex, but to a lesser degree than for noradrenergic innervation. Specific binding of muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate and the β-adrenergic receptor antagonist [3H]dihydroalprenolol was reduced 25% and 29% respectively in treated cortex. Thus, MAM treatment at 15 DG severely reduces intrinsic neuronal populations including GABAergic and glutamatergic neurons, and produces a shrunken cortex relatively hyperinnervated by noradrenergic and cholinergic neurons. MAM-induced micro-encephaly is a useful model system for producing relatively selective lesions of telencephalic neurons and for study of altered neurochemical relationships following developmentally incurred brain damage.