Johnston M V, Coyle J T
Brain Res. 1979 Jul 6;170(1):135-55. doi: 10.1016/0006-8993(79)90946-6.
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 beta-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 microencephaly 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.
当发育中的大鼠在妊娠第15天（DG）暴露于乙酸甲基氧化偶氮甲醇（MAM）时，会导致前脑小头畸形。这种强效烷基化剂对分裂细胞具有选择性细胞毒性。由于新皮质中不同的神经元群体在妊娠期间有丝分裂活动的时间差异很大，因此预计某些群体在接受治疗后会有不同程度的减少。对成长至成年的经处理大鼠的新皮质进行组织学检查发现，II-IV层有大量损失，更深层相对保留。萎缩的成年新皮质通过检测几种确定的突触前和突触后神经化学标记物进行进一步表征。GABA能神经元的总标记物大幅减少（谷氨酸脱羧酶减少71%，[3H]GABA突触体摄取减少63%，内源性GABA减少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，去甲肾上腺素能神经支配的总突触前标记物变化最小，但酪氨酸羟化酶浓度、[3H]去甲肾上腺素突触体摄取和内源性去甲肾上腺素分别增加了275%、130%和133%。萎缩皮质中胆碱能突触前标记物的浓度也增加了（胆碱乙酰转移酶增加97%，内源性乙酰胆碱增加64%），但增加程度低于去甲肾上腺素能神经支配。在经处理的皮质中，毒蕈碱胆碱能拮抗剂[3H]喹核苄酯和β-肾上腺素能受体拮抗剂[3H]二氢心得舒的特异性结合分别减少了25%和29%。因此，在妊娠第15天进行MAM处理会严重减少包括GABA能和谷氨酸能神经元在内的固有神经元群体，并产生一个萎缩的皮质，该皮质由去甲肾上腺素能和胆碱能神经元相对过度支配。MAM诱导的小头畸形是一个有用的模型系统，可用于产生相对选择性的端脑神经元损伤，并用于研究发育过程中发生脑损伤后神经化学关系的改变。
