Synaptic Plasticity-Regulated Gene Expression: a Key Event in the Long-Lasting Changes of Neuronal Function

Abstract

"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 Ca 2؉ signals via NMDA receptors and L-type voltage-dependent Ca 2؉ 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.

Expression of Synaptic Proteins in the Hippocampus and Spatial Learning in Chicks following Prenatal Auditory Stimulation

“…It has been shown that brain-derived neurotrophic factor (BDNF) induces the transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation of neurons of the visual cortex in culture [61] . It is also known that transcriptional activation of the BDNF gene is regulated by phosphorylation of CREB (cAMP response element-binding protein) at Ser-133 and may contribute to activity-dependent neuronal survival [62] . In our earlier study, we have observed an increase in the levels of CREB mRNA and phosphorylated CREB (p-CREB) protein as well as BDNF mRNA and BDNF protein following the same sound stimulation protocol [63] .…”

2-Decenoic acid ethyl ester possesses neurotrophin-like activities to facilitate intracellular signals and increase synapse-specific proteins in neurons cultured from embryonic rat brain

“…4A). BDNF gene is known to be upregulated by CREB activation (6,25). However, NT-3 gene expression is not up-regulated by Ca 2+ entry, suggesting that it is under CREB-independent regulation.…”

“…However, NT-3 gene expression is not up-regulated by Ca 2+ entry, suggesting that it is under CREB-independent regulation. In fact, both specificity protein (Sp)3 and Sp4 are transcription factors that bind to the NT-3 promoter (25). NGF transcription is regulated via an activating protein 1 (AP-1) binding site in the first intron of the NGF gene (4), suggesting NGF to be regulated CREB-independently.…”

<b>Brain Plasticity, Signal Transduction and Epigenesis: a Missing Link Revealed</b>

“…In this context exercise, by means of excitatory glutamatergic transmission, would trigger BDNF mRNA expression following the activation of glutamate AMPA and NMDA receptors and the influx of Ca 2+ through voltage-dependent L-type channels generally located in neuronal dendritic spines. Transcriptional activation of the BDNF gene is commonly regulated by a key transcription factor denominated cAMP response element-binding protein (CREB) in cooperation with the upstream stimulatory factor (Tabuchi et al, 2002;Tabuchi, 2008). Once BDNF is released and bound to its tyrosine-kinase receptor B (TrkB), the receptor dimerizes and its intracytoplasmic domains may then phosphorylate each other at different tyrosine residues.…”