靶向细胞间粘附分子（ICAM5）矫正脆性X综合征小鼠行为障碍和內嗅-齿状回神经通路发育异常

脆性X综合征（FXS）是最常见的智力发育迟滞综合征，其神经环路发育异常及智力障碍的机制所知甚少，治疗欠缺。我们前期证明细胞间粘附分子 5（ICAM5）是RNA结合蛋白FMRP的直接靶分子，ICAM5在FXS动物模型Fmr1 KO小鼠端脑多区域异常增高，延迟树突棘成熟，提示ICAM5在FXS中枢突触联接建立与重塑中发挥重要作用，其表达改变可能导致神经环路发育异常。本项目首次提出ICAM5过表达介导的突触发育异常可能参与FXS智力障碍。拟用稀疏标记和神经环路示踪、光选择性激活兴奋性神经元、MED64微阵列记录海马脑片LTP和全细胞膜片钳记录突触后AMPA/ NMDA受体激活，以及免疫印记、流式微球分析和多种行为观察，确定ICAM5是矫正Fmr1 KO小鼠內嗅-海马齿状回突触发育异常及相关行为障碍的新靶点，并阐明其结构、功能和分子基础，从传统受体以外的角度，为治疗FXS提供崭新的思路。

Fragile X Syndrome (FXS) is the most common inherited form of mental retardation. Leading hypotheses of FXS pathogenesis emphasize faulty neural circuit refinement during early postnatal critical periods of neurodevelopment. However alterations in neural circuit development are poorly-established in Fmr1 knockout (KO) mouse models of FXS. Our previous work is the first report of Fmr1 KO mice to express excessive intercellular cell adhesion molecule (ICAM5), a molecule involved in neural development and implicated in FXS through binding to FMRP, and the increased ICAM5 in the brains of Fmr1 KO mice is associated with impaired behaviors. Excess ICAM5 protein may be a common molecular mechanism underlying altered neural wiring in major causes of intellectual disability. But how such increased ICAM5 affect synaptic function and neural circuits remain incompletely understood. Here, we posit that the establishment, properties, and dynamics of synapses are governed by ICAM5，and elevated postsynaptic ICAM5 is related to synapse assembly dysfunction in entorhinal-hippocampal in a FXS. Therefore, in the present project, using a combination of sparse labeling, neural circuit tracing, photogenetic activation of excitatory neurons, MED64 microarray and whole cell patch clamp, as well as behavioral analyses, and cutting edge biological techniques, we will demonstrate that Fmr1 KO mice exhibit abnormal behaviors including impaired fear learning and memory, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the ICAM5, along with disrupted dendritic development, synaptic pathology, and altered entorhinal-hippocampal neural circuit. Reduction of ICAM5 by shRNA reversed cognitive deficits, and as well as entorhinal-hippocampal circuit. These data would demonstrate a novel role for ICAM5 in learning, memory, and neural circuit formation and a potential neurobiological mechanism for FXS.