Whether neurons express major histocompatibility complex (MHC) class I genes has not been firmly established. The techniques of confocal laser microscopy, patch clamp electrophysiology, and reverse transcriptase-polymerase chain reaction were combined here to directly examine the inducibility of MHC class I genes in individual cultured rat hippocampal neurons. Transcription of MHC class I genes was very rare in neurons with spontaneous action potentials. In electrically silent neurons, transcription was noted, with expression of beta(2)-microglobulin under tighter control than in class I heavy chain molecules. Surface expression of class I molecules occurred only in electrically silent neurons treated with interferon gamma. Immunosurveillance by cytotoxic T cells may be focused on functionally impaired neurons.