Fig. 12.
Proposed cascade of epigenetic events responsible for anesthesia-induced neurotoxicity during critical stages of synaptogenesis. Anesthesia promotes excessive cAMP-responsive element-binding protein (CBP) degradation (fragmentation from 270 to 148 kDa), thus down-regulating full-length CBP protein with consequent decrease in its histone acetyltransferase (HAT) activity. This decreased HAT activity, in turn, causes histone-3 hypoacetylation, an epigenetic change that leads to more condensed chromatin structure less conducive to transcription of the target genes brain-derived neurotrophic factor (BDNF) and cellular Finkel-Biskis-Jinkins murine sarcoma virus osteosarcoma oncogene (c-Fos). BDNF and c-Fos are critical for neuronal morphological development. An impairment in proper dendritic arborization leads to impaired neuronal connectivity resulting in faulty formation of neuronal circuits and compromised synaptic neurotransmission. GA = general anesthesia; mRNA = messenger RNA.