Neuroligin Function in vivo: Implications for Autism and Mental Retardation

跨突触细胞黏附分子中神经连接蛋白(NL)家族成员的功能丧失突变 与人类自闭症和智力低下有牵连。自闭症的动物模型已经严重 有限，但这些人类基因发现提供了一条新的途径来开发真正的小鼠模型，至少 人类自闭症或智力低下的亚型。 NLS是突触后跨膜蛋白，与突触前β-Neurexins结合以诱导形成 兴奋性和抑制性突触与控制兴奋性/抑制性(E/I)突触平衡 神经元。E/I平衡的改变被认为在自闭症和精神疾病的发病机制中具有重要作用 智力迟缓。NL在自闭症和精神障碍的体内和神经行为异常中的确切作用 然而，发育迟缓仍有待确定。 我们将通过NL的电生理和行为特征来确定神经连接素在体内的作用 基因敲除，人类疾病突变敲除，以及在后续研究中，条件基因敲除小鼠。驾驶 假设是NL基因缺陷的小鼠，或者携带已知的NL疾病相关突变的小鼠，将表现出 行为差异与人类自闭症或智力低下的行为差异一致，并且这些行为差异 差异将与E/I平衡或大脑皮质回路突触功能的特定异常有关 活着。将实现以下具体目标： 1.确定NL3疾病相关突变或缺失是否会导致自闭症和精神分裂症 与发育迟缓相关的行为异常。 2.确定NL3或NL3疾病相关突变的缺失是否会导致兴奋性和 抑制性突触连接和功能。 3.确定NL3或NL3疾病相关突变的缺失是否会改变诱导的阈值 海马区NMDA受体依赖的突触可塑性。

Loss-of-function mutations in members of the neuroligin (NL) family of trans-synaptic cell adhesion molecules have been implicated in human autism and mental retardation. Animal models of autism have been severely limited, but these human genetic findings provide a novel path to develop bona fide mouse models of at least a subtype of human autism or mental retardation. NLs are postsynaptic transmembrane proteins that bind presynaptic beta-neurexins to induce formation of excitatory and inhibitory synapses and to control excitatory/inhibitory (E/I) synapse balance in cultured neurons. Alterations in E/I balance have been proposed as important in pathogenesis of autism and mental retardation. The precise role of NL in vivo and in neurobehavioral abnormalities in autism and mental retardation, however, remains to be determined. We will determine the role of neuroligin in vivo using electrophysiologic and behavioral characterization of NL knockout, human disease mutation knockin, and, in follow-up studies, conditional knockout mice. The driving hypothesis is that mice deficient in NL genes, or carrying known disease-linked mutations in NL, will exhibit behavioral differences consistent with those in human autism or mental retardation, and that these behavioral differences will be associated with specific abnormalities in E/I balance or synaptic function in cortical circuits in vivo. The following specific aims will be addressed: 1. To determine whether NL3 disease-linked mutation or deletion of NL3 result in autism and mental retardation-related behavioral abnormalities. 2. To determine whether deletion of NL3 or NL3 disease-linked mutations result in altered excitatory and inhibitory synaptic connectivity and function. 3. To determine whether deletion of NL3 or NL3 disease-linked mutations alter the threshold for inducing NMDA-receptor-dependent synaptic plasticity in the hippocampus.