Jin Sung-Ha, Kim Hyung J T, Harris D Christopher, Thomas Steven A
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Comp Neurol. 2004 Sep 20;477(3):300-9. doi: 10.1002/cne.20263.
A fundamental question in the formation of the nervous system is the extent to which a neurotransmitter contributes to the development of the neurons that synthesize and release it. A complementary question is whether neurotransmitter signaling contributes to the development of postsynaptic targets. Prior studies have suggested that adrenergic signaling may promote adrenergic neuronal proliferation or survival and may be critical for the postnatal development of the cerebellum. To test these possibilities genetically, we studied mice that are unable to synthesize norepinephrine and epinephrine (NE/E), the endogenous adrenergic receptor ligands, due to a disruption the gene for dopamine beta-hydroxylase. These mice develop postnatally in the absence of NE/E. Here we report that the adrenergic neurons of these mutant mice are present in normal numbers and locations and exhibit typical innervation patterns throughout the central nervous system (CNS), as assessed by immunostaining for tyrosine hydroxylase and the NE transporter. Furthermore, cerebellar cortical development (size, foliation, layering, cell number, and position), which proceeds to a large degree postnatally, is unaltered in the mutants. These results indicate that the fate and innervation pattern of the adrenergic neurons, as well as the development of the cerebellum, do not depend on postnatal signaling by NE/E. The results also suggest that when restoration of adrenergic signaling is performed in this mutant mouse model (by administering a synthetic precursor of NE), reversal of phenotypes is due to the synthesis and release of NE/E from adrenergic terminals that are distributed normally within the CNS.
神经系统形成过程中的一个基本问题是，神经递质在多大程度上有助于合成和释放它的神经元的发育。一个相关问题是神经递质信号传导是否有助于突触后靶点的发育。先前的研究表明，肾上腺素能信号传导可能促进肾上腺素能神经元的增殖或存活，并且可能对小脑的出生后发育至关重要。为了从基因层面验证这些可能性，我们研究了由于多巴胺β-羟化酶基因缺失而无法合成去甲肾上腺素和肾上腺素（NE/E）（内源性肾上腺素能受体配体）的小鼠。这些小鼠在出生后没有NE/E的情况下发育。在此我们报告，通过酪氨酸羟化酶和NE转运体的免疫染色评估，这些突变小鼠的肾上腺素能神经元数量和位置正常，并且在整个中枢神经系统（CNS）中表现出典型的神经支配模式。此外，在很大程度上在出生后进行的小脑皮质发育（大小、叶状结构、分层、细胞数量和位置）在突变体中未发生改变。这些结果表明，肾上腺素能神经元的命运和神经支配模式以及小脑的发育并不依赖于NE/E的出生后信号传导。结果还表明，当在这个突变小鼠模型中恢复肾上腺素能信号传导时（通过给予NE的合成前体），表型的逆转是由于NE/E从正常分布在CNS内的肾上腺素能终末合成和释放所致。
