Acquisition of Contextual Discrimination Involves the Appearance of a RAS-GRF1/p38 Mitogen-activated Protein (MAP) Kinase-mediated Signaling Pathway That Promotes Long Term Potentiation (LTP)

Jin, Shan-Xue; Arai, Junko; Tian, Xuejun; Kumar‐Singh, Rajendra; Feig, Larry A.

doi:10.1074/jbc.m113.471904

Cited by 26 publications

(49 citation statements)

References 49 publications

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“…Expression of this form of AMPARs in the hippocampus enhances LTP (Jia et al 1996;Wiltgen et al 2010;Sanderson et al 2012;Jin et al 2013), which utilizes a distinct pathway compared with a traditional NMDARdependent LTP (Jia et al 1996;Wiltgen et al 2010;Jin et al 2013;Kim et al 2015a). In this study, we reveal that KO animals show enhanced hippocampus-dependent contextual fear learning and memory (Fig.…”

Section: +mentioning

confidence: 57%

“…A previous study shows that CP-AMPAR expression in the hippocampus is required for contextual discrimination (Jin et al 2013), thus CP-AMPAR expression in the KO hippocampus could increase contextual discrimination, leading to enhanced fear learning. Since GluA1-pS845 levels are lower in the KO amygdala (Fig.…”

Section: +mentioning

confidence: 94%

“…All AMPARs in GluA2 KO are GluA1 homomeric channels, which allows hippocampal LTP to be independent of NMDARs (Jia et al 1996;Wiltgen et al 2010), and impairs NMDAR-mediated learning (Wiltgen et al 2010). Conversely, the hippocampus of cGKII KO that expresses CP-AMPARs alongside GluA2-containing AMPARs exhibit NMDAR-dependent LTP (Sanderson et al 2012;Jin et al 2013;Kim et al 2015a). It is possible that expression of CP-AMPARs in the presence or absence of GluA2 would activate distinct pathways that result in different behavior outcomes.…”

Section: +mentioning

confidence: 99%

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Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

et al. 2016

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Phosphorylation of GluA1, a subunit of AMPA receptors (AMPARs), is critical for AMPAR synaptic trafficking and control of synaptic transmission. cGMP-dependent protein kinase II (cGKII) mediates this phosphorylation, and cGKII knockout (KO) affects GluA1 phosphorylation and alters animal behavior. Notably, GluA1 phosphorylation in the KO hippocampus is increased as a functional compensation for gene deletion, while such compensation is absent in the prefrontal cortex. Thus, there are brain region-specific effects of cGKII KO on AMPAR trafficking, which could affect animal behavior. Here, we show that GluA1 phosphorylation levels differ in various brain regions, and specific behaviors are altered according to region-specific changes in GluA1 phosphorylation. Moreover, we identified distinct regulations of phosphatases in different brain regions, leading to regional heterogeneity of GluA1 phosphorylation in the KO brain. Our work demonstrates region-specific changes in GluA1 phosphorylation in cGKII KO mice and corresponding effects on cognitive performance. We also reveal distinct regulation of phosphatases in different brain region in which region-specific effects of kinase gene KO arise and can selectively alter animal behavior.

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confidence: 57%

Section: +mentioning

confidence: 94%

Section: +mentioning

confidence: 99%

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Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

et al. 2016

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“…Previous characterization of GRF1-knockout (KO) mice has documented a specific implication of this protein in memory formation (Brambilla et al, 1997;Giese et al, 2001), postnatal growth (Itier et al, 1998;Fernández-Medarde et al, 2002), pancreatic β-cell function and glucose homeostasis (Font de Mora et al, 2003;Manyes et al, 2014), and neurosensory processes and photoreception (Fernández-Medarde et al, 2007Hysi et al, 2010). By contrast, the study of Rasgrf2-null animals has demonstrated that GRF2 and GRF1 are not functionally overlapping regarding memory formation or body growth (Fernández-Medarde et al, 2002;Jin et al, 2013;Li et al, 2006) and has also documented that GRF2 plays specific functional roles in control of T-cell proliferation and signaling in lymphocyte proliferation, T-cell signaling responses and lymphomagenesis (Ruiz et al, 2007(Ruiz et al, , 2009. Recent studies of specifically affected human patient subpopulations support a role of GRF1 in predisposition to myopia and refractive errors of vision (Hysi et al, 2010) and of GRF2 in predisposition to addictive alcohol abuse (Easton et al, 2014;Schumann et al, 2011;Stacey et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

RasGRF2 controls nuclear migration in postnatal retinal cone photoreceptors

Jimeno

Gómez

Calzada

et al. 2016

Journal of Cell Science

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Detailed immunocytochemical analyses comparing wild-type (WT), GRF1-knockout (KO), GRF2-KO and GRF1/2 double-knockout (DKO) mouse retinas uncovered the specific accumulation of misplaced, 'ectopic' cone photoreceptor nuclei in the photoreceptor segment (PS) area of retinas from GRF2-KO and GRF1/2-DKO, but not of WT or GRF1-KO mice. Localization of ectopic nuclei in the PS area of GRF2-depleted retinas occurred postnatally and peaked between postnatal day (P)11 and P15. Mechanistically, the generation of this phenotype involved disruption of the outer limiting membrane and intrusion into the PS layer by cone nuclei displaying significant perinuclear accumulation of signaling molecules known to participate in nuclear migration and cytoskeletal reorganization, such as PAR3, PAR6 and activated, phosphorylated forms of PAK, MLC2 and VASP. Electroretinographic recordings showed specific impairment of cone-mediated retinal function in GRF2-KO and GRF1/2-DKO retinas compared with WT controls. These data identify defective cone nuclear migration as a novel phenotype in mouse retinas lacking GRF2 and support a crucial role of GRF2 in control of the nuclear migration processes required for proper postnatal development and function of retinal cone photoreceptors.

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“…We previously reported that RasGRF1 contributes to contextual discrimination by regulating a specific form of postsynaptic plasticity called high frequency long-term potentiation (HFS-LTP, (Jin et al, 2013) in the CA1 region of the hippocampus. Additionally, this signaling was dependent on p38 activation.…”

Section: Introductionmentioning

confidence: 99%

R-Ras contributes to LTP and contextual discrimination

2014

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The ability to discriminate between closely related contexts is a specific form of hippocampal-dependent learning that may be impaired in certain neurodegenerative disorders such as Alzheimer's and Down Syndrome. However, signaling pathways regulating this form of learning are poorly understood. Previous studies have shown that the calcium-dependent exchange factor Ras-GRF1, an activator of Rac, Ras and R-Ras GTPases, is important for this form of learning and memory. Moreover, the ability to discriminate contexts was linked to the ability of Ras-GRF1 to promote high-frequency stimulation (HFS)-LTP via the activation of p38 Map kinase. Here, we show that R-Ras is involved in this form of learning by using virally-delivered miRNAs targeting R-Ras into the CA1 region of dorsal hippocampus and observing impaired contextual discrimination. Like the loss of GRF1, knockdown of R-Ras in the CA1 also impairs the induction of HFS-LTP and p38 Map kinase. Nevertheless, experiments indicate that this involvement of R-Ras in HFS-LTP that is required for contextual discrimination is independent of Ras-GRF1. Thus, R-Ras is a novel regulator of a form of hippocampal-dependent LTP as well as learning and memory that is affected in certain forms of neurodegenerative diseases.

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Acquisition of Contextual Discrimination Involves the Appearance of a RAS-GRF1/p38 Mitogen-activated Protein (MAP) Kinase-mediated Signaling Pathway That Promotes Long Term Potentiation (LTP)

Cited by 26 publications

References 49 publications

Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

RasGRF2 controls nuclear migration in postnatal retinal cone photoreceptors

R-Ras contributes to LTP and contextual discrimination

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