Mohan Vishwa, Gomez Julia R, Maness Patricia F
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, United States.
Front Cell Dev Biol. 2019 Jan 31;7:9. doi: 10.3389/fcell.2019.00009. eCollection 2019.
Neuron-Glia related cell adhesion molecule (NrCAM) is a candidate autism risk factor that promotes axon guidance through cytoskeletal linkages in developing brain but its role in limbic circuitry has not been investigated. hybridization (ISH) and immunofluorescence staining showed that NrCAM is expressed in the developing amygdalar pathway of mouse embryos during outgrowth of projections in the stria terminalis, a major limbic tract that interconnects the central amygdala (CeA) with key targets in the bed nucleus of the stria terminalis (BNST). Analysis of fiber tracts in NrCAM mutant mice by Neurofilament protein immunohistochemistry showed pronounced defasciculation and misprojection of fibers in the ST. The defasciculation phenotype may result from impairment in NrCAM homophilic inter-axonal adhesion or axon repulsion from the secreted ligand Semaphorin 3F, which is expressed in limbic areas in proximity to the ST. Behavioral testing indicated that NrCAM null mice were impaired in context-dependent fear conditioning, in accord with altered amygdala-BNST connectivity, but displayed normal cued (tone-shock) conditioning. Results are consistent with the novel finding that NrCAM mediates fasciculation of axon fibers in the ST important for proper amygdalar-BNST circuitry and response to contextual fear conditioning.
神经元-胶质细胞相关细胞粘附分子（NrCAM）是一种自闭症风险候选因素，它在发育中的大脑中通过细胞骨架连接促进轴突导向，但其在边缘回路中的作用尚未得到研究。原位杂交（ISH）和免疫荧光染色显示，在终纹床核（BNST）的主要边缘束——终纹在小鼠胚胎发育中的杏仁核通路中，NrCAM在突起生长过程中表达，终纹将中央杏仁核（CeA）与终纹床核中的关键靶点相互连接。通过神经丝蛋白免疫组织化学对NrCAM突变小鼠的纤维束进行分析，结果显示终纹中纤维明显出现去束化和投射错误。这种去束化表型可能是由于NrCAM同源性轴突间粘附受损，或者是由于在终纹附近的边缘区域表达的分泌配体信号素3F对轴突产生排斥作用所致。行为测试表明，NrCAM基因敲除小鼠在情境依赖性恐惧条件反射方面存在缺陷，这与杏仁核-终纹床核连接性改变一致，但在线索（音调-电击）条件反射方面表现正常。这些结果与一项新发现一致，即NrCAM介导终纹中轴突纤维的束化，这对正确的杏仁核-终纹床核回路以及对情境恐惧条件反射的反应至关重要。
