neuronal activity influences CREB dynamics has been investigated in a new study from Osaka University, led by Nobuhiko Yamamoto,
Hironobu Kitagawa, Noriyuki Sugo and colleagues.
Neuronal activity mediates the formation of neuronal circuits in the
cerebral cortex. These processes are regulated by the transcription
factor CREB, which regulates gene expression in neuronal
activity-dependent processes. Neuronal activity enhances CREB-mediated
transcription but the mechanisms remain unclear.
‘Providing novel insights into the regulation of gene expression by neuronal activity, researchers have investigated how neuronal activity influences CREB dynamics.’
CREB binds to a cAMP response element (CRE) in the promoter region of
its target genes. Assembly and disassembly of CREB-CRE interactions
control spatiotemporal gene expression in the nucleus. However, how CREB
interacts with CRE in activity-dependent mechanisms is not known.Fluorescent-tagged CREB
constructs were expressed in primary cortical neurons and visualized by
staining fixed cells. Single CREB molecules were predominantly detected
in the nucleus and some were observed at sites where gene transcription
was taking place.
The movement of single CREB molecules in living cortical neurons was
monitored by real-time imaging. Interestingly, some CREB molecules
disappeared almost immediately while a fraction remained in the same
location for a longer duration. Using mutant forms of CREB that cannot
bind to CRE, the researchers showed that these CREB molecules were
interacting with CRE.
To investigate how neuronal activity affects CREB-CRE interactions
and subsequent gene transcription, the authors treated cortical neurons
with pharmacological agents that alter neuronal activity. Neuronal
activity did not affect the time that CREB resided in the nucleus.
Next, the research team investigated whether neuronal activity regulates
the spatial distribution of CREB in the nucleus. They stimulated
cortical neurons and monitored CREB localization by real-time imaging.
Interestingly, the number of locations where CREB resided for long
periods increased considerably after neuronal activation. These findings
indicated that neuronal activity increases CREB-CRE interactions in the
The findings provide novel insights into the regulation of gene
expression by neuronal activity. Based on the results of this study,
neuronal activity may contribute to CREB-dependent gene expression by
increasing the binding of CREB to specific genomic sites.