Intercelluar Bioactive Molecules in Neural Circuit

神经元通过各种各样的神经递质和受体相互交流。尽管存在这种巨大的多样性，但每种功能神经通路都可以通过其独特的递质和受体来识别。在发育过程中，神经递质/肽表型是如何在每个神经通路中指定的？由于神经递质或其受体的异常表达通常与各种神经系统疾病有关，因此其表型调节的重要性一直受到争论。我们之前已经证明，神经生长因子等扩散细胞间因子可以调节培养神经元的这种神经元表型。在本项目中，我们旨在利用神经营养因子或相关分子基因被破坏的突变小鼠，研究它们在体内对递质/受体表型的影响。基于我们之前在冷泉港实验室的友谊，我们与它的神经科学小组建立了这个合作项目，研究大量的这些突变小鼠。重点研究了嗜神经因子的基因及其靶分子；脑源性神经营养因子（BDNF）、Fyn、CREB、α - camk2和nos。分子生化和组织化学分析显示，神经营养因子突变体的各种神经递质及其受体和突触酶的表达均较低，反过来，酶突变体的神经营养因子水平异常。这些观察结果表明，神经营养因子和这些突触受体/酶在大脑发育过程中相互作用，并调节协同突触发育。

Neurons communicate with each other using a large variety of neurotransmitters and receptors. Despite this enormous diversity, each functional neural pathway can be recognized by its distinctive set of transmitters and receptors employed. How is the neurotransmitter/peptide phenotype specified in each neural pathway during development? The importance of their phenotypic regulation has been argumented since abnormal expression of neurotransmitters or their receptors are often associated with various neurological diseases.We have previously shown that diffusible intercellular factors such as nerve growth factor can regulate such neuronal phenotypes in cultured neurons. In this proposed project, we aimed at studying their in vivo influences on transmitter/receptor phenotypes using mutant mice whose genes of neurotrophins or related molecules are disrupted. Based on our previous friendship in Cold Spring Harbor Lovoratory, we have established this collaboration project with its neuroscience group to examine a large variety of these mutant mice. We have focused on genes of neurotropic factors as well as their target molecules ; brain-derived neurotrophic factor (BDNF), Fyn, CREB,alpha-CAMK2 and NOS.Molecular, biochemical and histochemical analyzes revealed that the neurotrophin mutant exhibited lower expression of various neurotransmitters, their receptors and the synaptic enzymes, and, in turn, the enzyme mutants contrained abnormal levels of neurotrophins. These observations suggest that neurotrophins and these synaptic receptors/enzymes interact with each other during brain development and regulate synergistic synaptic development.