Targeting PDZ to unravel early anesthetic exposure-produced cognitive dysfunction

描述（由申请人提供）：先前的临床队列研究和动物研究表明，早期暴露于麻醉剂是日后发生 学习障碍。然而，潜在的分子机制尚不清楚。一些证据表明，受损的海马神经发生和突触发生可能参与早期麻醉暴露产生长期认知障碍的机制，并且突触支架蛋白PSD-95 PDZ结构域介导的蛋白质-蛋白质相互作用和突触活动参与海马神经发生和突触发生的调节。我们以前的研究表明，PDZ结构域介导的蛋白质相互作用被临床相关浓度的吸入麻醉剂破坏。最近，我们发现，暴露出生后第7天（PND）大鼠异氟烷减少海马神经发生，抑制树突棘发育和突触可塑性，并损害学习和记忆功能。这些结果表明，PDZ相互作用和PDZ结构域介导的突触功能的破坏可能在早期麻醉麻醉药引起的长期认知障碍的发病机制中起重要作用。我们推测，早期暴露的新生大鼠吸入麻醉剂抑制神经发生和干扰突触发育中的海马突触PDZ的相互作用和PDZ域介导的突触功能，从而产生长期的神经认知功能障碍。为了解决这一假设，我们将确定突触PDZ相互作用和PDZ结构域介导的突触功能是否有助于异氟醚抑制神经发生和抑制突触发生的潜在机制（Aim 1）;我们将确定吸入麻醉剂异氟醚介导的PDZ结构域破坏在体外发育的海马神经元中的细胞生物学效应（Am 2）;我们将进一步确定突触PDZ相互作用的破坏和PDZ结构域介导的突触功能的损害是否有助于早期麻醉剂暴露后的长期认知损害（目的3）。拟议的研究将提供关键证据，以澄清早期麻醉剂暴露是否通过抑制PDZ相互作用调节的海马神经发生和突触发生而产生长期认知障碍。这些数据将揭示新生儿麻醉神经毒性的发病机制。该提案的总体目标是证明突触PDZ相互作用和PDZ结构域介导的突触功能在早期麻醉剂暴露产生的长期认知障碍中的作用。

DESCRIPTION (provided by applicant): Previous clinical cohort studies and animal studies have shown that early exposure to anesthetics is a significant risk factor for later development of learning disabilities. However, the underlying molecular mechanism is unclear. Several lines of evidence have indicated that impaired hippocampal neurogenesis and synaptogenesis may be involved in the mechanisms by which early anesthetic exposure produces long-term cognitive impairment, and that synaptic scaffolding protein PSD-95 PDZ domain-mediated protein-protein interactions and synaptic activities are involved in the regulation of neurogenesis and synaptogenesis in the hippocampus. Our previous studies have demonstrated that PDZ domain-mediated protein interactions are disrupted by clinically relevant concentrations of inhaled anesthetics. Recently, we showed that exposing postnatal day (PND) 7 rats to isoflurane diminishes hippocampal neurogenesis, inhibits dendritic spine development and synaptic plasticity, and impairs learning and memory function. These results suggest that the disruption of PDZ interactions and PDZ domain-mediated synaptic function may play important roles in the pathogenesis of early anesthetic exposure-produced long-term cognitive impairment. We hypothesize that early exposure of neonatal rats to inhaled anesthetics inhibits neurogenesis and interferes with synaptogenesis by disrupting synaptic PDZ interactions and PDZ domain-mediated synaptic function in the developing hippocampus, thereby producing long-term neurocognitive dysfunction. To address this hypothesis, we will determine whether synaptic PDZ interactions and PDZ domain-mediated synaptic function contribute to the mechanism underlying isoflurane suppression of neurogenesis and inhibition of synaptogenesis (Aim 1); we will determine the cell biological effects of inhaled anesthetic isoflurane-mediated PDZ domain disruption in developing hippocampal neurons in vitro (Am 2); we will further determine whether the disruption of synaptic PDZ interactions and the impairment of PDZ domain-mediated synaptic function contributes to long-term cognitive impairment after early anesthetic exposure (Aim 3). The proposed studies will provide critical evidence to clarify whether early anesthetic exposure produces long-term cognitive impairment by inhibiting PDZ interaction-regulated hippocampal neurogenesis and synaptogenesis. The data will shed new light on the pathogenesis of neonatal anesthetic neurotoxicity. The overall goal of this proposal is to demonstrate the roles of synaptic PDZ interactions and PDZ domain-mediated synaptic function in early anesthetic exposure- produced long-term cognitive impairment.