Noebels J L
Nature. 1984;310(5976):409-11. doi: 10.1038/310409a0.
One strategy for deciphering inherited neurological disease is to examine the expression of individual genes controlling the assembly and physiology of specific cell groups within the developing mammalian central nervous system (CNS). This neurogenetic approach, using defined single-locus mutations arising on coisogeneic mouse strains, has recently been used to analyse a major class of neuronal membrane diseases involving abnormal excitability, the epilepsies, and to identify examples of hereditary variation in signalling properties at central synapses. An interesting mutation, the Tottering (tg) gene, causes a delayed onset, recessive neurological disorder in the mouse featuring a stereotyped triad of ataxia, intermittent myoclonus and cortical spike-wave discharges accompanied by behavioural absence seizures which resemble petit mal epilepsy. Axon branches of the locus coeruleus, a noradrenergic brain-stem nucleus, hyperinnervate specific target regions of the tg brain. The number of parent coerulean perikarya is unaffected, indicating a true proliferation of the terminal axonal arbor. With the exception of this unusually precise error of axonal growth, no other cytopathology has been identified in the tg brain. Here I present evidence that selective lesions of the central noradrenergic axons early in development limit the expression of the disease.
破译遗传性神经疾病的一种策略是检查控制发育中的哺乳动物中枢神经系统（CNS）内特定细胞群组装和生理功能的单个基因的表达。这种神经遗传学方法，利用同基因小鼠品系上出现的特定单基因座突变，最近已被用于分析一类主要的涉及异常兴奋性的神经元膜疾病——癫痫，并确定中枢突触信号特性的遗传变异实例。一个有趣的突变，蹒跚（tg）基因，在小鼠中导致一种迟发性、隐性神经疾病，其特征是共济失调、间歇性肌阵挛和皮质棘波放电的刻板三联征，并伴有类似失神小发作癫痫的行为性失神发作。蓝斑是一个去甲肾上腺素能脑干核，其轴突分支过度支配tg脑的特定靶区域。蓝斑母细胞的数量未受影响，表明终末轴突树确实发生了增殖。除了这种异常精确的轴突生长错误外，在tg脑中未发现其他细胞病理学变化。在此，我提供证据表明，发育早期中枢去甲肾上腺素能轴突的选择性损伤会限制该疾病的表达。
