Targeting PDZ to unravel early anesthetic exposure-produced cognitive dysfunction

Johns Hopkins University, Baltimore MD

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Abstract

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.