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The \u2018synaptic tag\u2019 theory proposes that gene products can only be captured and utilized at synapses that have been \u2018tagged\u2019 by previous activity. The mechanisms underlying synaptic tagging, and its activity dependence, are largely undefined. Previously, we reported that low\u2010frequency stimulation (LFS) decreases the stability of L\u2010LTP in a cell\u2010wide manner by impairing synaptic tagging. We show here that a phosphatase inhibitor, okadaic acid, blocked homosynaptic and heterosynaptic inhibition of L\u2010LTP by prior LFS. In addition, prior LFS homosynaptically and heterosynaptically impaired chemically induced synaptic facilitation elicited by forskolin\/3\u2010isobutyl\u20101\u2010methylxanthine, suggesting that there is a cell\u2010wide dampening of cAMP\/protein kinase A (PKA) signaling concurrent with phosphatase activation. We propose that prior LFS impairs expression of L\u2010LTP by inhibiting synaptic tagging through its actions on the cAMP\/PKA pathway. In support of this notion, we show that hippocampal slices from transgenic mice that have genetically reduced hippocampal PKA activity display impaired synaptic capture of L\u2010LTP. An inhibitor of PKA, KT\u20105720, also blocked synaptic capture of L\u2010LTP. Moreover, pharmacological activation of the cAMP\/PKA pathway can produce a synaptic tag to capture L\u2010LTP expression, resulting in persistent synaptic facilitation. Collectively, our results show that PKA is critical for synaptic tagging and for input\u2010specific L\u2010LTP. PKA\u2010mediated signaling can be constrained by prior episodes of synaptic activity to regulate subsequent L\u2010LTP expression and perhaps control the integration of multiple synaptic events over time.<\/jats:p>","DOI":"10.1111\/j.1460-9568.2006.04707.x","type":"journal-article","created":{"date-parts":[[2006,4,5]],"date-time":"2006-04-05T13:46:57Z","timestamp":1144244817000},"page":"1784-1794","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Metaplasticity of the late\u2010phase of long\u2010term potentiation: a critical role for protein kinase A in synaptic tagging"],"prefix":"10.1111","volume":"23","author":[{"given":"Jennie Z.","family":"Young","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Isiegas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ted","family":"Abel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter V.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,4,5]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81904-2"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/266736a0"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.9.5280"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.25.15020"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00657-8"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(80)90509-3"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1973.sp010273"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5371.1940"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90400-6"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(92)90803-H"},{"key":"e_1_2_7_13_1","doi-asserted-by":"crossref","first-page":"13 111","DOI":"10.1016\/S0021-9258(18)45175-7","article-title":"Inhibition of intracellular cAMP\u2010dependent protein kinase using mutant genes of the regulatory type I subunit","volume":"262","author":"Clegg C.H.","year":"1987","journal-title":"J. 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