Neuroligin Function in vivo: Implications for Autism and Mental Retardation

描述(由申请人提供)：跨突触细胞黏附分子的神经连接蛋白(NL)家族成员的功能丧失突变与人类自闭症和智力低下有关。自闭症的动物模型受到了严重的限制，但这些人类基因发现提供了一条新的途径，可以开发出至少一个亚型的人类自闭症或智力低下的真正的小鼠模型。NLS是突触后跨膜蛋白，可与突触前β-Neurexins结合，诱导兴奋性和抑制性突触的形成，控制兴奋性/抑制性(E/I)突触的平衡。E/I平衡的改变被认为在自闭症和精神发育迟滞的发病机制中具有重要作用。然而，NL在体内的确切作用以及在自闭症和智力低下的神经行为异常中的作用仍有待确定。我们将通过NL基因敲除、人类疾病突变敲除的电生理学和行为学特征，以及后续研究中的条件性基因敲除小鼠，来确定神经连接素在体内的作用。驱动假说是，缺乏NL基因或携带已知NL疾病相关突变的小鼠将表现出与人类自闭症或智力低下患者一致的行为差异，并且这些行为差异将与体内E/I平衡或皮质回路突触功能的特定异常有关。具体目标如下：1.确定NL3疾病相关突变或缺失是否会导致自闭症和精神发育迟滞相关的行为异常。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的改变。3.确定NL3或NL3疾病相关突变的缺失是否改变了诱导海马区NMDA受体依赖的突触可塑性的阈值。公共卫生相关性：自闭症谱系障碍和智力低下是常见的，涉及社会互动或认知功能的衰弱障碍，在部分患者中临床重叠。最近，神经连接蛋白家族跨突触细胞黏附分子的功能缺失突变已被认为与人类自闭症和智力低下有关。具有神经连接蛋白基因改变的小鼠将被描述为自闭症和智力低下的潜在动物模型，以努力更好地了解这些衰弱疾病的原因和治疗。

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.