General Anesthesia Causes Long-Lasting Disturbances in the Ultrastructural Properties of Developing Synapses in Young Rats
- 531 Downloads
Common general anesthetics administered to young rats at the peak of brain development cause widespread apoptotic neurodegeneration in their immature brain. Behavioral studies have shown that this leads to learning and memory deficiencies later in life. The subiculum, a part of the hippocampus proper and Papez’s circuit, is involved in cognitive development and is vulnerable to anesthesia-induced developmental neurodegeneration. This degeneration is manifested by acute substantial neuroapoptotic damage and permanent neuronal loss in later stages of synaptogenesis. Since synapse formation is a critical component of brain development, we examined the effects of highly neurotoxic anesthesia combination (isoflurane, nitrous oxide, and midazolam) on ultrastructural development of synapses in the rat subiculum. We found that this anesthesia, when administered at the peak of synaptogenesis, causes long-lasting injury to the subicular neuropil. This is manifested as neuropil scarcity and disarray, morphological changes indicative of mitochondria degeneration, a decrease in the number of neuronal profiles with multiple synaptic boutons and significant decreases in synapse volumetric densities. We believe that observed morphological disturbances of developing synapses may, at least in part, contribute to the learning and memory deficits that occur later in life after exposure of the immature brain to general anesthesia.
KeywordsIsoflurane Nitrous oxide Midazolam Synaptogenesis Subiculum Neurotoxicity
This study was supported by the NIH/NICHD HD 44517 (to V.J-T.) and Harold Carron endowment (to V.J-T). V.J-T. is an Established Investigator of the American Heart Association. The authors thank Jan Redick, Lisa Carter, and the Advanced Microscopy Facility at the University of Virginia Health System for technical assistance with electron microscopy.
- Day M, Wang Z, Ding J, An X, Ingham CA, Shering AF, Wokosin D, Ilijic E, Sun Z, Sampson AR, Mugnaini E, Deutch AY, Sesack SR, Arbuthnott GW, Surmeier DJ (2006) Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nat Neurosci 9:251–259CrossRefPubMedGoogle Scholar
- Loepke AW, Istaphanous GK, McAuliffe JJIII, Miles L, Hughes EA, McCann JC, Harlow KE, Kurth CD, Williams MT, Vorhees CV, Danzer SC (2009) The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 108:90–104CrossRefPubMedGoogle Scholar
- Paxinos G, Watson C (1944) The rat brain in Stereotaxic coordinates. Academic Press, Sydney, AustraliaGoogle Scholar