The goal of this project is to elucidate the long-term consequences of general anesthetics on synapse development and function, and to develop therapeutic strategies to prevent synaptic and learning deficits caused by early exposure to anesthesia. Anesthetics are commonly used for surgical operations in infants and young children. Recent studies suggest that repeated and prolonged anesthetic exposure, during the period of extensive synaptogenesis, can lead to learning and behavioral impairments later in life. However, the mechanisms by which anesthetics cause long-lasting deficits in neural circuits and learning impairments remain unknown. In this application, we will investigate the effects of single and repeated exposure to anesthetics on synaptic plasticity and function at specific stages of brain development. By using in vivo two- photon microscopy in combination with newly-generated glutamate and calcium sensors, we will determine whether repeated exposure to anesthetics during early postnatal development has long-lasting detrimental impacts on learning-dependent synaptic plasticity and function later in life. In addition, we will test the hypothesis that the adverse effects of anesthetics such as ketamine or sevoflurane are due to persistent hypofunction of glutamatergic neurotransmission and that pharmacological enhancement of the activities of ?- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or N-methyl-D-aspartate (NMDA) receptors would alleviate such effects. The proposed experiments will allow us to gain important mechanistic insights into how early exposure to anesthesia causes learning and behavioral impairments. They will also help establish novel treatment strategies directed at rescuing the detrimental effects of anesthesia on the developing brain.
Millions of infants and young children are exposed to anesthetic agents each year, but the deleterious effects of anesthesia on the developing brain are poorly understood. This project will determine how repeated exposure to general anesthetics affects synapse development and plasticity in the mouse cortex using a combination of techniques including in vivo high-resolution imaging, biochemistry and behavioral studies. The proposed studies will provide important mechanistic insights into anesthesia-induced learning impairments and help the development of new treatment strategies.