CREB can get you depressed.

Many neuronal systems exhibit both a protein synthesis–independent early phase of synaptic plasticity and a distinct late phase of synaptic plasticity, which lasts many hours or days and requires new protein synthesis and gene transcription. Similarly, memory has both a short-term component that is independent of protein synthesis and a long-term component that requires translation and transcription. The transcription factor CREB is a prominent candidate molecule for mediating the switch from early to late phases of synaptic plasticity (reviewed by 6xMartin, K.C. and Kandel, E.R. Neuron. 1996; 17: 567–570Abstract | Full Text | Full Text PDF | PubMed | Scopus (142)See all References, 8xYin, J.C. and Tully, T. Curr. Opin. Neurobiol. 1996; 6: 264–268Crossref | PubMed | Scopus (260)See all References; Silva et al. 1998xSilva, A.J., Kogan, J.H., Frankland, P.W., and Kida, S. Annu. Rev. Neurosci. 1998; 21: 127–148Crossref | PubMed | Scopus (881)See all ReferencesSilva et al. 1998). CREB-dependent transcription is activated by multiple protein kinases, including cAMP-dependent protein kinase (PKA), Ca2+/CaM-dependent protein kinases I and IV (CaMKI and CaMKIV), RSK2, and other protein kinases downstream of the MAP kinase cascade. In all cases, phosphorylation of CREB on Ser-133 is thought to be critical for CREB interaction with the CREB binding protein (CBP), which then recruits the basic transcription machinery to the CREB-regulated promoter.Studies in diverse systems, including Aplysia, Drosophila, and mice, have implicated CREB in synaptic plasticity and learning and memory (Martin and Kandel 1996xMartin, K.C. and Kandel, E.R. Neuron. 1996; 17: 567–570Abstract | Full Text | Full Text PDF | PubMed | Scopus (142)See all ReferencesMartin and Kandel 1996; Yin et al., 1996; Silva et al. 1998xSilva, A.J., Kogan, J.H., Frankland, P.W., and Kida, S. Annu. Rev. Neurosci. 1998; 21: 127–148Crossref | PubMed | Scopus (881)See all ReferencesSilva et al. 1998). In Aplysia, injection of phosphorylated CREB1 is sufficient to induce a long-term synaptic facilitation that lasts 24 hr. Drosophila that express a dominant-negative CREB mutant fail to learn an odor-specific memory task. Mice in which the α and δ isoforms of CREB have been deleted through homologous recombination show deficits in spatial learning and a decrease in the protein synthesis–dependent late phase of hippocampal LTP (but show normal early-phase LTP). In hippocampal neurons, CREB phosphorylation depends on complicated and interacting kinase cascades, involving an ERK/MAP kinase cascade, PKA (Impey et al. 1998xImpey, S., Obrietan, K., Wong, S.T., Poser, S., Yano, S., Wayman, G., Deloulme, J.C., Chan, G., and Storm, D.R. Neuron. 1998; 21: 869–883Abstract | Full Text | Full Text PDF | PubMed | Scopus (641)See all ReferencesImpey et al. 1998), and CaMKIV (Deisseroth et al. 1998xDeisseroth, K., Heist, E.K., and Tsien, R.W. Nature. 1998; 392: 198–202Crossref | PubMed | Scopus (458)See all ReferencesDeisseroth et al. 1998).So far, examples of CREB-mediated synaptic plasticity all involve the long-term enhancement of synaptic transmission (i.e., LTP and long-term facilitation). However, synapses also display long-term decreases in synaptic transmission, such as long-term depression (LTD) (see Linden and Connor 1995xLinden, D.J. and Connor, J.A. Annu. Rev. Neurosci. 1995; 18: 319–357Crossref | PubMedSee all ReferencesLinden and Connor 1995). Up until now, it had not been known whether CREB-regulated gene expression is also necessary for these inhibitory forms of synaptic plasticity. And if gene activation by CREB is required for long-term decreases in synaptic strength, what are the upstream signaling cascades that are needed for its recruitment? In this issue of Neuron, Ahn, Ginty, and Linden 1999xAhn, S., Ginty, D.D., and Linden, D.J. Neuron. 1999; 23: 559–568Abstract | Full Text | Full Text PDF | PubMed | Scopus (120)See all ReferencesAhn, Ginty, and Linden 1999 address these questions for the late, protein synthesis–dependent phase of LTD in cultured cerebellar Purkinje neurons.Cerebellar LTD was initially described as a prolonged decrease in synaptic transmission between parallel fibers of presynaptic granule cells and postsynaptic Purkinje neurons (Linden and Connor 1995xLinden, D.J. and Connor, J.A. Annu. Rev. Neurosci. 1995; 18: 319–357Crossref | PubMedSee all ReferencesLinden and Connor 1995). It is typically induced by pairing climbing fiber stimulation, which produces a large excitatory response in the Purkinje neuron, with granule cell stimulation. Although the mechanism of LTD induction in cerebellar brain slices is somewhat controversial, the Linden group has developed a simplified system to study LTD in isolated, cultured Purkinje neurons. Here, LTD of the postsynaptic response to iontophoretic application of glutamate is produced by pairing Purkinje neuron depolarization (mimicking climbing fiber stimulation) with activation of postsynaptic glutamate receptors (mimicking parallel fiber input). In this reduced system, LTD has both an early, protein synthesis–independent component and a late, protein synthesis–dependent component (Linden 1996xLinden, D.J. Neuron. 1996; 17: 483–490Abstract | Full Text | Full Text PDF | PubMed | Scopus (109)See all ReferencesLinden 1996). Now, the Linden group has gone on to show that late LTD in Purkinje neurons requires CREB activation and that this activation requires CaMKIV.Using particle-mediated gene transfection to provide a powerful molecular scalpel, Ahn et al. 1999xAhn, S., Ginty, D.D., and Linden, D.J. Neuron. 1999; 23: 559–568Abstract | Full Text | Full Text PDF | PubMed | Scopus (120)See all ReferencesAhn et al. 1999 find that expression of a dominant-negative form of CREB (which inhibits CREB binding to DNA and gene activation) blocks late, but not early, LTD. Dominant-negative forms of CaMKII and CaMKIV, as well as a calmodulin trap that is targeted to the nucleus, also inhibit late, but not early, LTD. The authors performed a series of careful control measurements to show that the inhibitory effects of these constructs were not due to inhibition of the early calcium signaling pathways necessary for the induction of LTD. A role for CaMKIV is consistent with studies in hippocampal neurons that show that Ca2+-dependent activation of CREB depends on the translocation of Ca2+/CaM to the nucleus, where it activates CaMKIV, the principle nuclear isoform of CaM kinase (Deisseroth et al. 1998xDeisseroth, K., Heist, E.K., and Tsien, R.W. Nature. 1998; 392: 198–202Crossref | PubMed | Scopus (458)See all ReferencesDeisseroth et al. 1998). Inhibition of other protein kinase cascades implicated in hippocampal LTP, such as PKA and p42/p44 MAP kinases, failed to block LTD in the Purkinje neurons.These results leave several questions open. Does the LTD-inducing protocol stimulate CREB phosphorylation on Ser-133 and does it activate CREB-mediated gene transcription? Is such phosphorylation directly mediated by CaMKIV or does this kinase act through other signaling pathways? Is CREB activation required for late LTD that is induced by synaptic stimulation in cerebellar slices? Do mice deficient in CREB exhibit deficits in cerebellar-dependent motor learning? Finally, is CREB also required for hippocampal late LTD? And if so, how can activation of a single transcription factor contribute to both synaptic potentiation and depression? Clearly, CREB's new role as a regulator of synaptic depression provides a powerful potentiating stimulus for future studies.