Mechanisms of synaptic and behavioral dysfunction after postnatal anesthesia

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Over 4 million infants and young children undergo general anesthesia (GA) every year in the US. Experimental evidence suggests that several mammalian species may suffer neurodegeneration, followed by long-lasting cognitive impairment, when exposed to common intravenous and inhaled anesthetics during critical stages of brain development. Recent studies also document disruption of sleep-wake behavior following GA with volatile anesthetics. To date, the mechanisms underlying the behavioral dysfunctions observed after GA remain incompletely understood and the effects of an early anesthetic exposure on synaptic function have not been explored in detail. Thus, the long term objectives of this proposal are to establish how exposure to GA alters synaptic plasticity, synaptic networking and behavioral output in the developing hippocampus and to decipher the mechanisms of GA-induced synaptic dysregulation. We address the specific hypothesis that a key component of the neurotransmitter release machinery, synapsin I, features decisively in the pathophysiology of GA-induced synaptic and cognitive dysfunction. This project encompasses three specific aims. In Specific Aim 1, we test the molecular effects of GA on the expression of pre-synaptic neurotransmitter release machinery components. This is achieved by western blot and qPCR quantification of several key components of the machine for vesicle release. In Specific Aim 2, we test the cellular effects of GA-induced impairment of the release machinery on synaptic transmission and plasticity. This is achieved by systematic electrophysiology experiments of basal synaptic transmission, plasticity, excitability and networking. In Specific Aim 3, we test the effects of anesthetics on learning, memory and sleep-wake behavior, using the Barnes maze, fear conditioning test and quantitative electroencephalographic analysis of sleep-wake patterns. Collectively, the proposed studies will provide new understanding of the molecular and cellular mechanisms of GA-induced synaptic dysregulation and behavioral dysfunction, and the rationale for new therapeutic strategies to prevent or improve cognitive, sleep-wake and other behavioral developmental dysfunctions after GA exposure. As a result of my training and research experience, I have the expertise necessary to successfully carry out this work. I assembled a cadre of senior investigators who are participating enthusiastically in my mentoring and my Chair has committed to me the protected time, all of the facilities and equipment that are needed to develop into a successful translational research scientist. My short term objective is to use this Award to acquire new skills to pursue my own niche of research, focusing on the role of sleep in anesthesia- induced cognitive dysfunction in the young and aging brain, and on the role of the synaptic fusion mechanism in neurological disorders and imbalances of neurotransmission. My long-term career objective is to become an independent fully extramurally funded clinician research scientist by ultimately successfully competing for R01 support from the NIH.