Neuroligin Function in vivo: Implications for Autism and Mental Retardation

描述（由申请人提供）：神经胶质素（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。自闭症的动物模型一直受到严重限制，但这些人类遗传学的发现为开发至少一种人类自闭症或智力迟钝亚型的真正小鼠模型提供了一条新途径。NLs是突触后跨膜蛋白，与突触前β -神经素结合，诱导兴奋性和抑制性突触的形成，并控制培养神经元中兴奋性/抑制性（E/I）突触的平衡。E/I平衡的改变在自闭症和智力迟钝的发病机制中起重要作用。然而，NL在体内以及在自闭症和智力迟钝的神经行为异常中的确切作用仍有待确定。我们将利用NL敲除、人类疾病突变敲除蛋白的电生理和行为特征，以及在后续研究中对条件敲除小鼠的研究，确定神经素在体内的作用。驱动假说是，缺乏NL基因的小鼠，或携带NL已知疾病相关突变的小鼠，将表现出与人类自闭症或智力迟钝一致的行为差异，这些行为差异将与体内E/I平衡或皮层回路突触功能的特定异常有关。将讨论以下具体目标：确定NL3疾病相关突变或NL3缺失是否会导致自闭症和智力迟钝相关的行为异常。2. 确定NL3或NL3疾病相关突变的缺失是否导致兴奋性和抑制性突触连通性和功能的改变。3. 确定NL3或NL3疾病相关突变的缺失是否会改变海马诱导nmda受体依赖性突触可塑性的阈值。公共卫生相关性：自闭症谱系障碍和智力迟钝是常见的，在一部分患者中涉及社会互动或认知功能的衰弱性障碍与临床重叠。最近，跨突触细胞粘附分子的神经素家族成员的功能丧失突变被认为与人类自闭症和智力迟钝有关。神经素基因改变的小鼠将被定性为自闭症和智力迟钝的潜在动物模型，以更好地了解这些衰弱性疾病的原因和治疗方法。

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.