Inducible Enhancement of Memory Storage and Synaptic Plasticity in Transgenic Mice Expressing an Inhibitor of ATF4 (CREB-2) and C/EBP Proteins

Chen, Amy; Muzzio, Isabel A.; Malleret, Gaël; Bartsch, Dušan; Verbitsky, Miguel; Pavlidis, Paul; Yonan, Amanda L.; Vronskaya, Svetlana; Grody, Michael B; Cepeda, Ivan L.; Gilliam, T. Conrad; Kandel, Eric R.

doi:10.1016/s0896-6273(03)00501-4

Cited by 254 publications

(198 citation statements)

References 63 publications

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“…Intriguingly, the Aplysia homologue of ATF4 has been referred to as a 'memory suppressor gene' 217 and mice with reduced ATF4 expression have enhanced hippocampal synaptic plasticity and memory storage. 218 Thus, interaction with ATF4 provides one possible mechanism by which DISC1 may modulate hippocampal function, aspects of which have been reported to be influenced by DISC1 genotype. 25 ATF5 is another cAMP-responsive transcription factor that interacts with DISC1.…”

Section: Disc1 Interaction With Atf4 and Atf5mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: Disc1 Interaction With Atf4 and Atf5mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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“…Studies on a variety of different forms of synaptic plasticity have suggested a link between messenger RNA translation and learning and memory (Kandel, 2001). Phosphorylated eIF2a (p-eIF2a) reduces general protein synthesis, but facilitates the mRNA translation of the transcriptional modulator ATF4 (Harding et al, 2000), which inhibits synaptic plasticity and behavioral learning by repressing CREB activity (Chen et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Choi

Kim

Shin

et al. 2007

Neuropsychopharmacol

259

179

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Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNAdependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 a and caspase 12 activation induced by amyloid b peptide 1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 a were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid b peptide 1-42 -infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid b peptide 1-42 -infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 a is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.

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“…Protein synthesis is highly regulated at the level of initiation by numerous translational control molecules, including the eukaryotic initiation factor 2 (eIF2) (Sonenberg and Dever 2003). Although phosphorylation of the a subunit of eIF2 inhibits general translation, it selectively stimulates the translation of the transcriptional modulator activating transcription factor 4 (ATF4) (Vattem and Wek 2004), which plays a role as a repressor of cAMP response element-binding protein (CREB)-mediated synaptic plasticity (Bartsch et al 1995;Abel et al 1998;Chen et al 2003). Previously, it was shown that reduction of eIF2a phosphorylation in mice lacking the eIF2a kinase general control nonderepressible 2 (GCN2) and in heterozygous knockin mice with a mutation on serine 51 of eIF2a results in a lowered threshold for inducing long-lasting late-phase long-term potentiation (L-LTP) (Costa-Mattioli et al 2005.…”

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confidence: 99%

The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression

Trinh

Kaphzan

et al. 2014

Learn. Mem.

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The proper regulation of translation is required for the expression of long-lasting synaptic plasticity. A major site of translational control involves the phosphorylation of eukaryotic initiation factor 2 a (eIF2a) by PKR-like endoplasmic reticulum (ER) kinase (PERK). To determine the role of PERK in hippocampal synaptic plasticity, we used the Cre-lox expression system to selectively disrupt PERK expression in the adult mouse forebrain. Here, we demonstrate that in hippocampal area CA1, metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) is associated with increased eIF2a phosphorylation, whereas stimulation of early-and late-phase long-term potentiation (E-LTP and L-LTP, respectively) is associated with decreased eIF2a phosphorylation. Interesting, although PERK-deficient mice exhibit exaggerated mGluR-LTD, both E-LTP and L-LTP remained intact. We also found that mGluR-LTD is associated with a PERK-dependent increase in eIF2a phosphorylation. Our findings are consistent with the notion that eIF2a phosphorylation is a key site for the bidirectional control of persistent forms of synaptic LTP and LTD and suggest a distinct role for PERK in mGluR-LTD.

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Inducible Enhancement of Memory Storage and Synaptic Plasticity in Transgenic Mice Expressing an Inhibitor of ATF4 (CREB-2) and C/EBP Proteins

Cited by 254 publications

References 63 publications

The DISC locus in psychiatric illness

The DISC locus in psychiatric illness

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression

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