Activity-dependent Transcriptional Activation and mRNA Stabilization for Cumulative Expression of Pituitary Adenylate Cyclase-activating Polypeptide mRNA Controlled by Calcium and cAMP Signals in Neurons

Although it has been established that an activity-dependent gene transcription is induced by the calcium (Ca2+) signals in neurons, it is unclear how the specific mRNA moieties are transiently accumulated in response to synaptic transmission which evokes multiple intracellular signals including Ca2+ and cAMP ones. The expression of pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide, is controlled by Ca2+ signals evoked via membrane depolarization in neurons, and, in cultured rat cortical neuronal cells, we found that the Ca2+ signal-mediated activation of the PACAP gene promoter was critically controlled by a single cAMP-response element (CRE) located at around –200, to which the CRE-binding protein predominantly bound. The Ca2+ signal-induced expression of PACAP mRNA was enhanced by forskolin, which evokes cAMP signals. In support, the PACAP gene promoter was synergistically enhanced by Ca2+ and cAMP signals through the CRE, accompanying a prolonged activation of extracellular signal-related protein kinase 1/2 and CRE-binding protein. On the other hand, sole administration of forskolin markedly reduced the cellular content of PACAP mRNA, which was restored by the addition of Ca2+ signals. We found that the stability of PACAP mRNA was increased in response to Ca2+ signals but not that of activity-regulated cytoskeleton-associated protein (Arc) mRNA, indicating an activity-dependent stabilization of specific mRNA species in neurons, which can antagonize the regulation mediated by cAMP signals. Thus, the transcriptional activation and mRNA stabilization are coordinately regulated by Ca2+ and cAMP signals for the cumulative expression of PACAP mRNA in neurons. Although it has been established that an activity-dependent gene transcription is induced by the calcium (Ca2+) signals in neurons, it is unclear how the specific mRNA moieties are transiently accumulated in response to synaptic transmission which evokes multiple intracellular signals including Ca2+ and cAMP ones. The expression of pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide, is controlled by Ca2+ signals evoked via membrane depolarization in neurons, and, in cultured rat cortical neuronal cells, we found that the Ca2+ signal-mediated activation of the PACAP gene promoter was critically controlled by a single cAMP-response element (CRE) located at around –200, to which the CRE-binding protein predominantly bound. The Ca2+ signal-induced expression of PACAP mRNA was enhanced by forskolin, which evokes cAMP signals. In support, the PACAP gene promoter was synergistically enhanced by Ca2+ and cAMP signals through the CRE, accompanying a prolonged activation of extracellular signal-related protein kinase 1/2 and CRE-binding protein. On the other hand, sole administration of forskolin markedly reduced the cellular content of PACAP mRNA, which was restored by the addition of Ca2+ signals. We found that the stability of PACAP mRNA was increased in response to Ca2+ signals but not that of activity-regulated cytoskeleton-associated protein (Arc) mRNA, indicating an activity-dependent stabilization of specific mRNA species in neurons, which can antagonize the regulation mediated by cAMP signals. Thus, the transcriptional activation and mRNA stabilization are coordinately regulated by Ca2+ and cAMP signals for the cumulative expression of PACAP mRNA in neurons. It is widely accepted that activity-dependent gene transcription in neurons is transiently induced by the Ca2+ signals evoked via glutamatergic synaptic transmission and plays a key role in establishing a long-term neuronal plasticity. Such a Ca2+ signal-mediated activation of gene transcription has fully been demonstrated with the brain-derived neurotrophic factor (1Tao X. Finkbeiner S. Arnold D.B. Shaywitz A.J. Greenberg M.E. Neuron. 1998; 20: 709-726Abstract Full Text Full Text PDF PubMed Scopus (1299) Google Scholar, 2Tabuchi A. Nakaoka R. Amano K. Yukimine M. Andoh T. Kuraishi Y. Tsuda M. J. Biol. Chem. 2000; 275: 17269-17275Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar) and c-fos (3Sheng M. McFadden G. Greenberg M.E. Neuron. 1990; 4: 571-582Abstract Full Text PDF PubMed Scopus (880) Google Scholar, 4Ghosh A. Ginty D.D. Bading H. Greenberg M.E. J. Neurobiol. 1994; 25: 294-303Crossref PubMed Scopus (279) Google Scholar) genes, in which the cAMP-response element (CRE) 1The abbreviations used are: CRE, cAMP-response element; PACAP, pituitary adenylate cyclase activating polypeptide; CREB, cAMP-responsive element-binding protein; RT, reverse transcription; APV, dl-amino-5-phosphonovalerate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Arc, activity-regulated cytoskeleton-associated protein; EF1α, human elongation factor 1α; ERK, extracellular signal-regulated kinase; MAP, mitogen-activated protein; PKA, cAMP-dependent protein kinase; IBMX, isobutylmethylxanthine; CRE-LE, CRE-like element; cPKA, catalytic protein kinase A subunit.-binding protein (CREB) is commonly involved. For this Ca2+ signaling in neurons, the ERK/mitogen-activated protein (MAP) kinase pathway is a major route that leads to the activation of CREB through phosphorylation of Ser-133 (5Rosen L.B. Ginty D.D. Weber M.J. Greenberg M.E. Neuron. 1994; 12: 1207-1221Abstract Full Text PDF PubMed Scopus (601) Google Scholar, 6Shaywitz A.J. Greenberg M.E. Annu. Rev. Biochem. 1999; 68: 821-861Crossref PubMed Scopus (1797) Google Scholar). In addition, Impey et al. (7Impey S. Obrietan K. Wong S.T. Poser S. Yano S. Wayman G. Deloulme J.C. Chan G. Storm D.R. Neuron. 1998; 21: 869-883Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar) have reported that cross-talk between ERK1/2 and cAMP-dependent protein kinase (PKA), which are activated by Ca2+ and cAMP signals, attains a synergistic activation of CREB-dependent transcription in neurons. This coupling of both signaling pathways has also been suggested to contribute to the formation of long-lasting synaptic plasticity (8Morozov A. Muzzio I.A. Bourtchouladze R. Van-Strien N. Lapidus K. Yin D. Winder D.G. Adams J.P. Sweatt J.D. Kandel E.R. Neuron. 2003; 39: 309-325Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar). However, it is still unclear how the cumulative expression of particular mRNA species responsible for synaptic plasticity is controlled transcriptionally and/or post-transcriptionally in response to synaptic transmission. Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the vasoactive intestinal polypeptide/secretin/glucagon family and was first isolated from the ovine hypothalamus (9Miyata A. Arimura A. Dahl R.R. Minamino N. Uehara A. Jiang L. Culler M.D. Coy D.H. Biochem. Biophys. Res. Commun. 1989; 164: 567-574Crossref PubMed Scopus (1686) Google Scholar). PACAP, which is synthesized as a precursor of 175 amino acids, is processed to its bioactive forms, PACAP38 and PACAP27 (10Li M. Shuto Y. Somogyvari-Vigh A. Arimura A. Neuroendocrinology. 1999; 69: 217-226Crossref PubMed Scopus (28) Google Scholar), which bind to at least two types of receptors, PAC1 and VPAC1/2 (11Hashimoto H. Ishihara T. Shigemoto R. Mori K. Nagata S. Neuron. 1993; 11: 333-342Abstract Full Text PDF PubMed Scopus (247) Google Scholar, 12Spengler D. Waeber C. Pantaloni C. Holsboer F. Bockaert J. Seeburg P.H. Journot L. Nature. 1993; 365: 170-175Crossref PubMed Scopus (1123) Google Scholar). The binding of PACAP to these receptors triggers several intracellular signaling pathways, resulting in versatile biological functions (13Vaudry D. Gonzalez B.J. Basille M. Yon L. Fournier A. Vaudry H. Pharmacol. Rev. 2000; 52: 269-324PubMed Google Scholar) such as neuronal survival (14Villalba M. Bockaert J. Journot L. J. Neurosci. 1997; 17: 83-90Crossref PubMed Google Scholar, 15Tabuchi A. Koizumi M. Nakatsubo J. Yaguchi T. Tsuda M. Neurosci. Res. 2001; 39: 85-93Crossref PubMed Scopus (39) Google Scholar) and synaptic plasticity (16Otto C. Kovalchuk Y. Wolfer D.P. Gass P. Martin M. Zuschratter W. Grone H.J. Kellendonk C. Tronche F. Maldonado R. Lipp H.P. Konnerth A. Schutz G. J. Neurosci. 2001; 21: 5520-5527Crossref PubMed Google Scholar). The rat PACAP gene consists of six exons including an alternative exon IA and IB and four exons encoding the coding region, and a variety of alternative transcripts are produced in neurons (17Yamamoto K. Hashimoto H. Hagihara N. Nishino A. Fujita T. Matsuda T. Baba A. Gene (Amst.). 1998; 211: 63-69Crossref PubMed Scopus (68) Google Scholar, 18Tabuchi A. Koizumi M. Tsuda M. Neuroreport. 2001; 12: 1181-1186Crossref PubMed Scopus (8) Google Scholar, 19Cummings K.J. Gray S.L. Simmons C.J. Kozak C.A. Sherwood N.M. Mol. Cell. Endocrinol. 2002; 192: 133-145Crossref PubMed Scopus (14) Google Scholar). It has been established that the expression of the PACAP gene is activated by the Ca2+ signals in neurons (15Tabuchi A. Koizumi M. Nakatsubo J. Yaguchi T. Tsuda M. Neurosci. Res. 2001; 39: 85-93Crossref PubMed Scopus (39) Google Scholar, 20Brandenburg C.A. May V. Braas K.M. J. Neurosci. 1997; 17: 4045-4055Crossref PubMed Google Scholar). On the other hand, the stabilization and de-stabilization of mRNA moieties are critical to control the level of PACAP mRNA in cells (21Harakall S.A. Brandenburg C.A. Gilmartin G.A. May V. Braas K.M. Ann. N. Y. Acad. Sci. 1998; 865: 367-374Crossref PubMed Scopus (17) Google Scholar). In this study, we first the located the PACAP gene promoter as a Ca2+ element and not synergistic activation induced by Ca2+ and cAMP signals through the and, the stabilization of PACAP mRNA was by these signals. We found an activity-dependent stabilization of mRNA that to the cumulative expression of PACAP mRNA in with the transcriptional activation synergistically induced by Ca2+ and cAMP signals. and from used for the from and and which with but not with other transcription the CREB family specific for with CREB, and CREB and CREB with CREB but not with other transcription which with CREB at the was also was used as a of rat cortical neurons from the of rat as A. K. Nakaoka R. C. Tsuda M. Biochem. Biophys. Res. Commun. 1998; PubMed Scopus Google Scholar). of by by and and the cells at cells in a The cells for in and the was with and was also at to the of The was with but of and of PACAP by was from the cultured cells was as (15Tabuchi A. Koizumi M. Nakatsubo J. Yaguchi T. Tsuda M. Neurosci. Res. 2001; 39: 85-93Crossref PubMed Scopus (39) Google Scholar). was in of first as a of reverse and of as by the reverse the was with of at for and used for as was in of of of and of the the four alternative exons exon exon of the rat PACAP and used to the coding region, and For the of rat activity-regulated cytoskeleton-associated protein (Arc) and For the rat glyceraldehyde-3-phosphate was and For of the at for at for at for at for for and a at for The of was for the by and the of the with a and was in an was in of of which was as and The as at for the at for at for and at for for a of with a of The for was from the and to the by from a For an was and the of PACAP transcripts to for and rat PACAP promoter gene was by The gene was isolated from rat cortical neurons. The with rat was in of of and of and The was the of and The of the rat PACAP gene promoter was to the that other reported L. H.J. J. A. Mol. 2000; PubMed Scopus Google Scholar, S.L. May V. Braas K.M. Ann. N. Y. Acad. Sci. 2000; PubMed Scopus (8) Google Scholar). For the promoter the PACAP promoter was by of with a including the of the rat PACAP gene promoter from the PACAP an control for the we used a the human elongation factor promoter A. Nakaoka R. Amano K. Yukimine M. Andoh T. Kuraishi Y. Tsuda M. J. Biol. Chem. 2000; 275: 17269-17275Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). For the we used a the human elongation factor promoter as an control A. H. T. H. Tsuda M. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The for the of was a and as a and and the The expression was by C. of and was in calcium as A. K. Nakaoka R. C. Tsuda M. Biochem. Biophys. Res. Commun. 1998; PubMed Scopus Google Scholar). the calcium by of in a with an of and to a For we used The was with and was the cells with for and For the and with and used as A. Nakaoka R. Amano K. Yukimine M. Andoh T. Kuraishi Y. Tsuda M. J. Biol. Chem. 2000; 275: 17269-17275Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, A. H. T. H. Tsuda M. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). For the of as an with of and of the was used for the and was used for the M. M. H. S. Ginty D.D. Acad. Sci. S. A. 2000; PubMed Scopus Google Scholar). of and the at in cells with and for as with P. W. Res. 1989; 17: PubMed Scopus Google Scholar). to the PACAP as reported A. H. T. H. Tsuda M. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of was at for in of and of of and of with a The binding was at for in of binding of of and of at for The protein was by the of For a of was used at a of the and in for at of at a membrane and the was with in The was with kinase kinase at and with for at CREB and ERK1/2 with the enhanced the of a of in as in the between by the with as the level of in of PACAP by first which transcripts encoding PACAP and increased in with membrane depolarization induced by in rat cortical neurons. The of to the transcripts exon and the exon transcripts the coding in the expression of the transcripts to the of cells to and this was for at least of with the transcripts of exon a single was with of exon and exon The expression of these transcripts the as in cells A. Koizumi M. Tsuda M. Neuroreport. 2001; 12: 1181-1186Crossref PubMed Scopus (8) Google Scholar), and in an the signals found to with of the neurons in not but the et al. (15Tabuchi A. Koizumi M. Nakatsubo J. Yaguchi T. Tsuda M. Neurosci. Res. 2001; 39: 85-93Crossref PubMed Scopus (39) Google of the the promoter of the PACAP we a both exon IA and exon IB in of a gene The of that the increased and the in was at at However, the the exon IA IB and promoter not the of the promoter of the PACAP these it is that responsible for the of the PACAP promoter are located in the of exon the we the of of a Ca2+ neurons, which was with and APV, for Ca2+ and the activation of PACAP promoter in the activation of promoter IA was was to the but a addition of these the Thus, both the Ca2+ through Ca2+ and for the activation of the PACAP of a for the of the the responsible for the Ca2+ of the we first the of a of of the promoter and found that the between and markedly reduced the activation of the promoter not in which a CRE-like element is the activation of the promoter is to the we the the In addition, we four the to the of these to the promoter in the of of markedly reduced the promoter and the the the and of not the of CREB to the binding to CRE-LE, we a which and its the family was to the binding the which not markedly with The addition of not the and that of CREB markedly the and the role of CREB in the Ca2+ signal-mediated activation of promoter of CREB rat cortical neurons with a Although of CREB not the activation that of a with an at the of the CREB that with the binding to and transcriptional activation of CREB S. M. S. D. Ginty D.D. C. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar), a with a in the binding that the binding of CREB D. M. M. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), the promoter activation induced by depolarization in of PACAP mRNA by cAMP a we the expression of PACAP exon transcripts the cells with depolarization and/or forskolin for in the level of the transcripts to and the of In to the level of the transcripts the addition of forskolin at at the and reduced for at least addition of depolarization with forskolin, markedly increased the expression of transcripts the sole addition of depolarization at and the The expression of transcripts not at the addition of and markedly the expression level of transcripts depolarization the of exon transcripts induced by depolarization is by the Ca2+ neurons through Ca2+ and of forskolin with depolarization enhanced the expression level with that by depolarization the level of which was also reduced in the of and APV, and reduced that by depolarization Thus, these that the addition of forskolin the level of PACAP in the of Ca2+ signals, but its can of the by the of with and the expression of exon transcripts was by depolarization and forskolin A and we the of administration of depolarization and forskolin the PACAP promoter activation the kinase pathway to the activation of CREB-dependent transcription in with the pathway (7Impey S. Obrietan K. Wong S.T. Poser S. Yano S. Wayman G. Deloulme J.C. Chan G. Storm D.R. Neuron. 1998; 21: 869-883Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar). in addition of depolarization and forskolin synergistically increased the promoter with that induced by This synergistic promoter activation was by addition of both and a for mitogen-activated extracellular signal-regulated kinase and for PKA, but by indicating an of both the kinase and pathways in the In of the of the the of the catalytic protein kinase A which was by of also induced the synergistic activation of the promoter the depolarization was The of the reduced the level of synergistic indicating a of to the synergistic activation of PACAP promoter IA of ERK1/2 and CREB and of ERK1/2 was markedly induced by the of cells with depolarization and by that with forskolin addition of both not the of ERK1/2 at the with that by depolarization but On the other hand, the phosphorylation at Ser-133 of CREB increased the of the level of which was the depolarization forskolin, and at least the of the of cells with depolarization and/or forskolin the expression level of exon transcripts which at least in not to that of promoter and it was that the Ca2+ and/or cAMP signals the of exon this we to the mRNA and for the level of in the of transcripts the addition of the of which was as On the other hand, the of transcripts at was which was that at This of the was by administration of and the of which from to and In was in the of mRNA, the of transcripts the addition of the mRNA expression was to a level that of the control not It was not the of the gene its by depolarization not of its long-term stability Although the addition of forskolin with to the of transcripts the addition of was with the of exon transcripts with the addition of In of depolarization and forskolin the of transcripts to the as was by depolarization the of which was to that the cAMP signals the expression level of PACAP mRNA, which can by the Ca2+ signals evoked via depolarization through a stabilization of PACAP In this we demonstrated that the PACAP was activated by Ca2+ signals through located between and of the promoter This was also responsible for the activation of induced by not and predominantly in the binding of CREB A and indicating that the located at around of PACAP is predominantly responsible for the of the promoter to the Ca2+ In the Ca2+ signal-mediated activation of brain-derived neurotrophic factor and c-fos gene not the but also other such as the factor binding element A. H. T. H. Tsuda M. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, X. G. M. C. Greenberg M.E. J. Neurosci. 2003; PubMed Google Scholar), element X. G. Greenberg M.E. Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), and element R. J. PubMed Scopus Google Scholar), are involved. In the activation of the promoter of the mRNA can controlled in an activity-dependent two which are by are responsible for the to the Ca2+ M. M. H. S. Ginty D.D. Acad. Sci. S. A. 2000; PubMed Scopus Google Scholar). Thus, the PACAP gene promoter is in of the of a single for the Ca2+ signal-mediated a Impey et al. (7Impey S. Obrietan K. Wong S.T. Poser S. Yano S. Wayman G. Deloulme J.C. Chan G. Storm D.R. Neuron. 1998; 21: 869-883Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar) reported that a synergistic activation of CREB-dependent transcription was by cross-talk between kinase and in and rat neuronal cells, which can induced by depolarization and This has also been suggested to contribute to the formation of long-lasting neuronal plasticity and (7Impey S. Obrietan K. Wong S.T. Poser S. Yano S. Wayman G. Deloulme J.C. Chan G. Storm D.R. Neuron. 1998; 21: 869-883Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar, A. Muzzio I.A. Bourtchouladze R. Van-Strien N. Lapidus K. Yin D. Winder D.G. Adams J.P. Sweatt J.D. Kandel E.R. Neuron. 2003; 39: 309-325Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, H. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In the study, we also the synergistic activation of induced by Ca2+ and cAMP signals evoked via depolarization and forskolin the In with the transcriptional activation of the the expression level of exon transcripts was by the of depolarization and forskolin this expression of transcripts was by the addition of and it is that the Ca2+ signals evoked via Ca2+ neurons are responsible for the of expression and the cAMP signals a role in the Ca2+ signal-mediated signaling The synergistic activation of the promoter was by of and but by a of activation of kinase and pathways for the synergistic promoter activation and, for the expression of exon transcripts induced by depolarization and forskolin The of the pathway was by the that the expression of catalytic of in the synergistic activation of the in the of Ca2+ signals Impey et al. (7Impey S. Obrietan K. Wong S.T. Poser S. Yano S. Wayman G. Deloulme J.C. Chan G. Storm D.R. Neuron. 1998; 21: 869-883Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar) demonstrated that the activation induced by forskolin was for the Ca2+ signal-induced of This coupling of the kinase and pathways a member of the of which is activated by H. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) and has been demonstrated to in neuronal plasticity (8Morozov A. Muzzio I.A. Bourtchouladze R. Van-Strien N. Lapidus K. Yin D. Winder D.G. Adams J.P. Sweatt J.D. Kandel E.R. Neuron. 2003; 39: 309-325Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar). the of the in ERK1/2 and CREB phosphorylation induced by depolarization and forskolin to to the synergistic activation of the PACAP promoter that other CREB in the synergistic of the responsible for the synergistic the protein which is activated by Ca2+ signals through the phosphorylation of by protein kinase and gene transcription via with transcriptional S. Y. Obrietan K. Wayman G.A. Storm D.R. Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). et al. J. PubMed Scopus Google Scholar) reported that protein in the synergistic activation of the human gene promoter induced by depolarization and forskolin in It is of particular that the in the expression of exon transcripts is induced by cAMP signals but by the addition of Ca2+ signals evoked via depolarization A and these that the cellular content of PACAP mRNA can regulated not at the level of transcription but also at that of mRNA in an activity-dependent In of we found that the of PACAP mRNA was prolonged by which was by the of Ca2+ neurons with and indicating that the Ca2+ signals are responsible for the of PACAP mRNA The of stability was also with brain-derived neurotrophic factor mRNA not but not with the mRNA which can to of the and Neuron. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). an activity-dependent stabilization of particular mRNA species in neurons, which can controlled by Ca2+ signals. On the other hand, the for the of cellular content of PACAP mRNA induced by forskolin A and is still unclear the of exon transcripts was not by administration of forskolin In cells, administration of forskolin increased the level of PACAP mRNA H. Hagihara N. K. K. N. S. Mori W. Y. Matsuda T. Baba A. J. 2000; PubMed Scopus Google Scholar), that the for the expression of PACAP mRNA controlled by cAMP signals of neurons. are to the for the of the cellular content of PACAP this controlled by cAMP signals, it was that of depolarization with forskolin restored the cellular content of PACAP mRNA to its level A and This not to to the synergistic activation of the of the transcripts was prolonged from to by depolarization in the of forskolin that the of mRNA at least in contribute to the of This also a of Ca2+ signals the cAMP signals the regulation of stabilization and de-stabilization of PACAP mRNA in neurons, which is to a of mRNA and in the neurons. neurons are of the Ca2+ signals in the of cAMP signals, the accumulated PACAP mRNA as by the in the cellular content of PACAP mRNA and in the of forskolin to a expression of PACAP mRNA in neurons in response to the Ca2+ signals. Thus, the cAMP its the transcriptional activation the Ca2+ signals are in neurons but a role in the cellular content of PACAP mRNA by the Ca2+ signals are these it can that the of activity-dependent transcriptional activation and mRNA which is controlled by Ca2+ signals but also by cAMP signals, plays an role in the cellular content of specific mRNA species in response to synaptic such as glutamatergic and to the formation of long-lasting neuronal plasticity. This is the first to an activity-dependent stabilization of specific mRNA not the activity-dependent gene transcription but also the activity-dependent of brain-derived neurotrophic factor mRNA M. A. J. Neurosci. 1997; 17: PubMed Google Scholar) has been the of particular mRNA species regulated in neurons in an activity-dependent Although such an activity-dependent mRNA stabilization not been the for this to the located in the of G. R. Cell. Full Text PDF PubMed Scopus Google Scholar), which are commonly found in with and in the of response gene including and J.D. Acad. Sci. S. A. 1999; PubMed Scopus Google Scholar). The PACAP gene can as an gene and we found element in the of the PACAP mRNA not of the for the activity-dependent mRNA stabilization the formation of synaptic plasticity.