Intercelluar Bioactive Molecules in Neural Circuit

神经元之间通过大量的神经递质和受体进行交流。尽管有如此巨大的多样性，每条功能神经通路都可以通过其所使用的独特的递质和受体集来识别。在发育过程中，神经递质/多肽的表型是如何在每条神经通路中被指定的？由于神经递质或其受体的异常表达经常与各种神经疾病相关，因此它们的表型调控的重要性已经被论证。我们先前已经证明，在培养的神经元中，可扩散的细胞间因子如神经生长因子可以调节这些神经元的表型。在这个拟议的项目中，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来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的友谊，我们与其神经科学小组建立了这个合作项目，以检查这些突变小鼠的种类繁多。我们重点研究了神经营养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表明，神经营养因子突变体表现出各种神经递质及其受体和突触酶的低表达，反过来，这些酶突变体抑制了神经营养因子的异常水平。这些观察表明，神经营养因子和这些突触受体/酶在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.