Neuroligin Function in vivo: Implications for Autism and Mental Retardation

描述（由申请人提供）：跨突触细胞粘附分子的神经连接素（NL）家族成员的功能丧失突变与人类自闭症和智力迟钝有关。自闭症的动物模型受到严重限制，但这些人类遗传学发现为开发至少一种人类自闭症或精神发育迟滞亚型的真正小鼠模型提供了一条新途径。NL是突触后跨膜蛋白，其结合突触前β-神经毒素以诱导兴奋性和抑制性突触的形成并控制培养的神经元中的兴奋性/抑制性（E/I）突触平衡。E/I平衡的改变被认为是自闭症和精神发育迟滞的重要发病机制。然而，NL在自闭症和精神发育迟滞的体内和神经行为异常中的确切作用仍有待确定。我们将通过NL基因敲除、人类疾病突变基因敲入以及条件性基因敲除小鼠的电生理学和行为学特征来确定神经配素在体内的作用。驱动假说是，小鼠缺乏NL基因，或携带已知的疾病相关的NL突变，将表现出与人类自闭症或精神发育迟滞一致的行为差异，并且这些行为差异将与体内皮质回路中E/I平衡或突触功能的特定异常相关。具体目标如下：1。确定NL 3疾病相关突变或NL 3缺失是否导致自闭症和精神发育迟滞相关行为异常。2.确定NL 3缺失或NL 3疾病相关突变是否导致兴奋性和抑制性突触连接和功能改变。3.确定NL 3缺失或NL 3疾病相关突变是否改变海马中诱导NMDA受体依赖性突触可塑性的阈值。公共卫生相关性：自闭症谱系障碍和精神发育迟滞是常见的、使人衰弱的疾病，涉及社会互动或认知功能，在一部分患者中具有临床重叠。最近，跨突触细胞粘附分子的神经连接素家族成员的功能缺失突变与人类自闭症和精神发育迟滞有关。具有神经连接素基因改变的小鼠将被表征为自闭症和精神发育迟滞的潜在动物模型，以更好地理解这些使人衰弱的疾病的原因和治疗。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Autism spectrum disorder and mental retardation are common, debilitating disorders involving social interaction or cognitive function with clinical overlap in a subset of patients. Recently, loss-of-function mutations in members of the Neuroligin family of trans-synaptic cell adhesion molecules have been implicated in human autism and mental retardation. Mice with genetic alterations of Neuroligin will be characterized as potential animal models of autism and mental retardation in an effort to better understand the cause and treatment of these debilitating disorders.