18 Mechanisms of buy AMD3100 neuroplasticity and the action of antidepressants What is the meaning of neuroplasticity? Neurobiologists call neuroplasticity the complex of the several processes whereby the brain senses, adapts, and responds to external and internal stimuli of various nature. We address here only molecular and cellular forms of neuroplasticity, which can be both structural and functional in nature; the manifestations of neuroplasticity under both these respects can assume many forms. We have schematically divided these forms into three major categories (listed in Table II): Inhibitors,research,lifescience,medical (i) modifications of gene expression; (ii)

modifications of synaptic transmission; (iii) neurogenesis. Table II Major cellular/molecular manifestations of neuroplasticity in the adult brain.

Neuroplasticity is the complex of many processes whereby the brain senses, adapts, and responds to external and internal stimuli of various nature. Modifications of gene expression: the role of CREB As addressed above, throughout the 1980s and 1990s the research on the mechanism of antidepressants Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical has moved from the study of monoamine neurotransmitter levels and sensitization state of membrane receptors to that of postreceptor intracellular signaling pathways. It has been shown that stimulation or inhibition of selected receptors for serotonin and noradrenaline induces adaptive changes in signaling pathways downstream of the receptors, including extensive crosstalk between pathways. In addition, many pathways are also activated by Ca-channels, glutamate receptors, and receptors for neurotrophins (Figure 2). A common Inhibitors,research,lifescience,medical downstream function of these intracellular pathways is the regulation of gene expression, through

the activation of protein families called transcription factors, that bind to specific domains in the promoter region of genes and regulate mRNA transcription. In this context, the most thoroughly studied factor, both in basic Inhibitors,research,lifescience,medical and psychopharmacological research, is the protein cAMP-response element binding protein (CREB). CREB function is involved in a wide range of brain mechanisms, either including learning and memory, induction of neurotrophic programs, outgrowth of neuronal processes, regulation of circadian rhythms, neurogenesis, pathophysiology of neuropsychiatrie and neurodegenerative disorders, and mechanisms of psychotropic drugs.19,23 CREB is regulated in multiple ways, including acetylation, ubiquitination, glycosylation, and SUMOylation, but the best known form of regulation is represented by phosphorylation at the Ser133 residue by multiple protein kinases.18,24-26 There is general agreement that chronic antidepressant treatments stimulate CREB function, although different results have been reported (sec below). It. has been shown that, rather than cAMPdependent pathways, other signaling cascades work as major regulators of CREB function in the brain.