Neuroligin Function in vivo: Implications for Autism and Mental Retardation

跨突触细胞粘附分子神经配素（NL）家族成员的功能缺失突变 与人类自闭症和智力迟钝有关。自闭症的动物模型已经严重 有限，但这些人类遗传学发现提供了一种新的途径，以发展真正的小鼠模型，至少有一个 人类自闭症或智力迟钝的亚型。 NLs是突触后跨膜蛋白，其结合突触前β-神经毒素以诱导突触后神经元的形成。 兴奋性和抑制性突触，并控制兴奋性/抑制性（E/I）突触平衡， 神经元E/I平衡的改变已被认为在自闭症和精神分裂症的发病机制中是重要的。 迟钝NL在体内以及在自闭症和精神疾病神经行为异常中的确切作用 然而，延迟仍有待确定。 我们将使用NL的电生理和行为特征来确定神经配素在体内的作用。 敲除、人类疾病突变敲入，以及在后续研究中，条件性敲除小鼠。驱动 一种假设是，NL基因缺陷的小鼠，或携带NL中已知的疾病相关突变的小鼠，将表现出 行为差异与人类自闭症或精神发育迟滞一致，这些行为差异 差异将与E/I平衡或皮层回路中突触功能的特定异常相关， vivo.将处理以下具体目标： 1.为了确定NL3疾病相关突变或NL3缺失是否导致自闭症和精神障碍， 与发育迟缓有关的行为异常 2.为了确定NL3的缺失或NL3疾病相关突变是否导致兴奋性和兴奋性的改变， 抑制性突触连接和功能。 3.为了确定NL3缺失或NL3疾病相关突变是否改变了诱导免疫应答的阈值， 海马中NMDA受体依赖性突触可塑性。

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.