Transcriptional activation is definitely a key link between neuronal activity and

Transcriptional activation is definitely a key link between neuronal activity and long-term synaptic plasticity. requires convergent activation of the CaM kinase and MAP kinase pathways. Although activation of PKA is not required for activity-dependent manifestation is definitely induced by cAMP in active neurons. CREB binds the promoter in vivo and partially regulates its activity-dependent manifestation. is an effector gene PF 477736 that is a target for transmission transduction pathways that mediate synaptic plasticity and thus may take part in an activity-regulated transcriptional system that directs long-term changes in synaptic contacts. Introduction Rules of gene manifestation is critical for bringing about long-term changes in synaptic contacts in response to neuronal activity (Goelet et al. 1986 Sheng and Greenberg 1990 Synaptic activation results in Ca2+ influx through N-methyl-d-aspartate (NMDA) receptors and L-type voltage-sensitive calcium channels (VSCCs) triggering several kinase pathways (Sheng et al. Rabbit Polyclonal to MARK2. 1991 Bading et al. 1993 Deisseroth et al. 1996 Three kinase pathways that play essential roles in various aspects of long-term plasticity are the Ca2+/calmodulin-dependent protein kinase (CaMK) the mitogen-activated protein kinase (MAPK) and the protein kinase A (PKA) pathways. These pathways activate transcription factors and cofactors such as PF 477736 cAMPresponsive element binding protein (CREB) CREB-binding protein (CBP) the ternary complex factor Elk-1 and Ca2+ response factor CaRF which in turn activate transcription of activity-regulated genes (Sheng et al. 1991 Xia et al. 1996 Chawla et al. 1998 Hu et al. 1999 Tao et al. 2002 Pharmacological and genetic studies have shown that the CaMK MAPK and PKA pathways and downstream factors like CREB are important for the electrophysiological paradigms of plasticity long-term potentiation and long-term depression as well as for learning and memory (reviewed in Yin and Tully 1996 Brandon et al. 1997 Silva et al. 1998 Impey et al. 1999 Orban et al. 1999 Soderling 2000 Sweatt 2001 Lisman et al. 2002 These pathways have also been shown to generate structural changes that can alter neuronal connectivity (Wu and Cline 1998 Wu et al. 2001 Redmond et al. 2002 Vaillant et al. 2002 Despite strong evidence linking kinase pathways and transcription factors to long-term plasticity little is known about how activation of these upstream regulatory molecules leads to long-term structural and functional changes at the synapse. Identifying effector genes regulated by these pathways is a crucial first step in elucidating the cellular processes that underlie plasticity. Among known activity-regulated genes only a handful have been shown to function as effector genes whose products directly mediate functional and structural changes at the synapse. Of these upstream regulation of only two genes and was isolated in a screen for activity-regulated genes induced by kainate-stimulated seizure in the rat dentate gyrus (Nedivi et al. 1993 and was subsequently shown to be sensitive to physiological stimuli such as light in the visual cortex (Nedivi et al. 1996 Its temporal and spatial expression patterns and its regulation by sensory input correlate with times and places of activity-dependent developmental plasticity (Corriveau et al. 1999 Nedivi et al. 2001 Lee and Nedivi 2002 When overexpressed in optic tectal neurons CPG15 induces elaboration of dendritic and axonal arbors and synaptic maturation by AMPA receptor insertion (Nedivi et al. 1998 Cantallops et al. 2000 These properties make a potential target for activation by signal transduction pathways that lead to long-term plasticity. PF 477736 Here we use cultured cortical neurons to investigate the pathways that lead to transcriptional activation of by synaptic activity. These studies demonstrate that is an immediate-early gene (IEG) regulated by multiple-signal transduction pathways transcription PF 477736 factors and promoter elements that have been strongly implicated in plasticity. Comparing the regulation of activity-induced effector genes will identify those salient properties of signaling pathways that mediate plasticity. Results cpg15 is an IEG induced by synaptic activity through NMDA receptors and L-type VSCCs To study transcriptional regulation of the gene we first examined whether expression in mouse primary neuronal cultures adequately reflects its in vivo.