Synaptic plasticity-regulated gene expression: a key event in the long-lasting changes of neuronal function.
"Neuronal activity"-dependent transcriptional activation is required for the long-lasting, functional changes that are involved in memory consolidation or drug addiction. Elucidation of the molecular mechanisms underlying the neuronal activity-dependent transcription of synaptic plasticity-related genes has helped towards understanding neuronal function and disorders as well in identifying new target molecules for drug design. In this study, we focused on neurotrophin and neuropeptide, which both have the ability to modulate neuronal survival and function. We also examined the molecular mechanisms by which underlying neurotrophin genes are regulated by neuronal activity. Brain-derived neurotrophic factor (BDNF) is a neurotrophin family member that has important roles in neuronal survival and plasticity as well as in psychiatric disorders. Transcriptional activation of the BDNF gene is commonly regulated by a key transcription factor, cAMP response element-binding protein (CREB), and this at least in part contributes to neuronal activity-dependent neuronal survival. Among at least four distinct promoters of the BDNF gene, promoters I and III are differentially activated by Ca2+ signals via NMDA receptors and L-type voltage-dependent Ca2+ channels. Especially, BDNF gene promoter I activation requires the cooperative binding of and upstream stimulatory factor (USF) and CREB to a CRE/USF binding site. By contrast, NT-3 gene transcription is regulated by Sp3/4. An important future direction will be to elucidate how long-lasting changes in neuronal plasticity are "epigenetically" and "structurally" controlled. Our studies on the relationships between long-lasting neuronal responses and gene expressions should help guide research into novel drugs for neuronal or psychiatric disorders.
Tabuchi
Akiko
A
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan. atabuchi@pha.u-toyama.ac.jp
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D009414:Nerve Growth Factors / Q000235:genetics*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020933:Neurotrophin 3 / Q000235:genetics; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics*; D013997:Time Factors; D014158:Transcription, Genetic
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D002118:Calcium