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Although coordinated molecular signaling through excitatory and modulatory neurotransmissions is critical for the induction of immediate early genes (IEGs), which lead to effective changes in synaptic plasticity, the intracellular mechanisms responsible remain obscure.

In cultures of rat cortical neurons, we found that stimulation of tyrosine receptor kinase B (TrkB) with brain-derived neurotrophic factor (BDNF) induced a biphasic expression of BDNF exon IV-IX mRNA, which became obvious 1-3 h (primary induction) and 24-72 h (delayed induction) after the stimulation, and characterized the delayed induction in relation to the mRNA expression of activity-regulated cytoskeleton-associated protein (Arc). Withdrawal of BDNF from the medium after stimulation for 3 h allowed the delayed induction, which was caused at the transcriptional level and dependent upon the initial contact between exogenously added BDNF and TrkB, the effect of which was time-and dose-dependent. The primary induction was controlled by the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) whereas the secondary induction by the calcium (Ca 2+ ) signaling pathway. The enhanced Arc or Zif268 mRNA expression was controlled by activation of the ERK/MAPK pathway, both of which were repressed by blocking the binding of endogenously synthesized BDNF to TrkB. Thus, robust stimulation of TrkB autonomously induces delayed BDNF mRNA expression in an activity-dependent manner in rat cortical neurons, resulting in the stimulation of Arc mRNA expression through endogenously synthesized BDNF, the process being orchestrated by the Ca 2+ and ERK/MAPK signaling pathways. Keywords: activity-regulated cytoskeleton-associated protein, brain-derived neurotrophic factor, calcium, extracellular signal-regulated kinase/mitogen-activated protein kinase, tyrosine receptor kinase B, Zif268.

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Abstract. Although it is widely accepted that an activity-dependent gene transcription is induced by the calcium (Ca 2+ ) signals in neurons, it is still unclear how the particular mRNA moieties are transiently accumulated in response to synaptic transmission that evokes multiple intracellular signals including Ca 2+ and cAMP ones. Promoters of the brain-derived neurotrophic factor (BDNF) and the pituitary adenylate cyclase-ativating polypeptide (PACAP) can commonly be activated through the cAMP-responsive element (CRE), to which the CRE-binding protein (CREB) predominantly bound. The activation of BDNF gene promoter I and III (BDNF-PI and -PIII, respectively) was mediated not only by the CREB but also by the upstream stimulatory factor, whereas that of PACAP gene promoter (PACAP-P) was mediated by only one CRE located at around −200. The PACAP-P was synergistically enhanced by Ca 2+ and cAMP signals through the CRE, whereas the BDNF-PI did not show such a synergistic activation upon the stimulation with both signals. In addition, we found that the half-lives of PACAP and BDNF mRNA were prolonged by the Ca 2+ influx into neurons but not that of Arc mRNA, indicating an activity-dependent stabilization of particular mRNA species in neurons. Thus, the activitydependent gene expression is co-ordinately controlled by Ca 2+ and cAMP signals not only at the transcriptional level but also at the post-transcriptional level for the cumulative mRNA expression in neurons.