Trophic effect of glutamate.

During development, Glu receptors and N-methyl-D-aspartate receptors in particular initiate a cascade of signal transduction events and gene expression changes primarily involving Ca(2+) ion-mediated signaling induced by activation of either Ca(2+) ion-permeable receptor channels or voltage-sensitive Ca(2+) ion channels. The consecutive activation of major protein kinase signaling pathways, such as Ras-MAPK/ERK and PI3-K-Akt, contributes to regulation of gene expression through the activation of key transcription factors, such as CREB, SRF, MEF-2, NF-kappaB. Metabotropic Glu receptors can also engage these signaling pathways and this may be mediated, in part, by transactivating receptor tyrosine kinases. Indirect effects of Glu receptor stimulation are due to the production and release of neurotrophic factors, such as brain derived neurotrophic factor and also involve glia-neuronal interaction through Glu-induced release of trophic factors from glia. The trophic effect of Glu receptor activation is developmental stage-dependent and may play an important role in determining the selective survival of neurons that made proper connections. During this sensitive developmental period interference with Glu receptor function may lead to widespread neuronal loss. However, NMDA receptor blockade-induced neurodegeneration can also occur in the adult brain. Depending on the stimulus strength, Glu receptors mediate biphasic effects. In addition to synaptic transmission, physiological stimulation of Glu receptors can mediate trophic effects and promote neuronal plasticity. Excessive stimulation is neurotoxic. Attention must, therefore, be paid to these features, when therapeutic manipulation of excitatory amino acid receptors is considered in the clinical setting.