HIPPOCAMPAL PLASTICITY INVOLVES EXTENSIVE GENE INDUCTION AND MULTIPLECELLULAR MECHANISMS

Long-term plasticity of the central nervous system (CNS) involves indu ction of a set of genes whose identity is incompletely characterized. To identify candidate plasticity-related genes (CPGs), we conducted an exhaustive screen for genes that undergo induction or downregulation in the hippocampus dentate gyrus (DG) following animal treatment with the potent glutamate analog, kainate. The screen yielded 362 upregulat ed CPGs and 41 downregulated transcripts (dCPGs). Of these, 66 CPGs an d 5 dCPGs are known genes that encode for a variety of signal transduc tion proteins, transcription factors, and structural proteins. Seven n ovel CPGs predict the following putative functions: cpg2-a dystrophin- like cytoskeletal protein; cpg4-a heat-shock protein: cpg16-a protein kinase; cpg20-a transcription factor; cpg21-a dual-specificity MAP-kin ase phosphatase; and cpg30 and cpg38-two new seven-transmembrane domai n receptors. Experiments performed in vitro and with cultured hippocam pal cells confirmed the ability of the cpg-21 product to inactivate th e MAP-kinase. To test relevance to neural plasticity, 66 CPGs were tes ted for induction by stimuli producing long-term potentiation (LTP). A pproximately one-fourth of the genes examined were upregulated by LTP. These results indicate that an extensive genetic response is induced in mammalian brain after glutamate receptor activation, and imply that a significant proportion of this activity is coinduced by LTP. Based on the identified CPGs, it is conceivable that multiple cellular mecha nisms underlie long-term plasticity of the nervous system.