Roles of NR2A and NR2B in the Development of Dendritic Arbor Morphology<i>In Vivo</i>

Ewald, Rebecca C.; Keuren‐Jensen, Kendall R. Van; Aizenman, Carlos D.; Cline, Hollis T.

doi:10.1523/jneurosci.5078-07.2008

Cited by 91 publications

(81 citation statements)

References 67 publications

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“…However, it has been difficult to address this hypothesis. Ectopic expression and knock down of the endogenous NR2A or NR2B subunits led to complex results (Ewald et al 2008), possibly because overexpression or knockdown experiments only shift the expression toward NR2A-or NR2B-rich receptor complexes, without eliminating the mixed NR1/NR2A/ NR2B receptor complexes that are expressed abundantly during development (Al-Hallaq et al 2007;Dunah and Standaert 2003;Sans et al 2000;Sheng et al 1994). The use of pharmacology also presents a challenge because the effectiveness of the NR2B-specific antagonist ifenprodil is significantly reduced when this subunit is part of the mixed NR1/NR2A/NR2B receptor complex (Williams 2001).…”

Section: Vscns As a Model System To Study Differential Roles Of Nr1nrmentioning

confidence: 99%

“…A requirement for NR2B in dendritic patterning in vivo was indeed shown recently with the use of mosaic analysis with double markers (MADM) to knock out NR2B in isolated single neurons (Espinosa et al 2009). To gain insights in the specific roles of NR2A-versus NR2B-containing receptors in dendrite development in single Xenopus tectal neurons, Ewald et al (2008) used overexpression and morpholine-mediated knockdown of NR2A and NR2B subunits. Although they showed that dendrite development was affected by manipulation of both NR2A and NR2B, the results are rather complex.…”

Section: Introductionmentioning

confidence: 99%

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Differential Roles of NMDA Receptor Subtypes NR2A and NR2B in Dendritic Branch Development and Requirement of RasGRF1

Sepúlveda¹,

Bustos²,

Inostroza³

et al. 2010

Journal of Neurophysiology

112

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Sepulveda FJ, Bustos FJ, Inostroza E, Zúñ iga FA, Neve RL, Montecino M, van Zundert B. Differential roles of NMDA receptor subtypes NR2A and NR2B in dendritic branch development and requirement of RasGRF1. J Neurophysiol 103: 1758 -1770, 2010. First published January 27, 2010 doi:10.1152/jn.00823.2009. Nmethyl-D-aspartate receptors (NMDARs) are known to regulate axonal refinement and dendritic branching. However, because NMDARs are abundantly present as tri-heteromers (e.g., NR1/NR2A/NR2B) during development, the precise role of the individual subunits NR2A and NR2B in these processes has not been elucidated. Ventral spinal cord neurons (VSCNs) provide a unique opportunity to address this problem, because the expression of both NR2A and NR2B (but not NR1) is downregulated in culture. Exogenous NR2A or NR2B were introduced into these naturally NR2-null neurons at 4 DIV, and electrophysiological recordings at 11 DIV confirmed that synaptic NR1NR2A receptors and NR1NR2B receptors were formed, respectively. Analysis of the dendritic architecture showed that introduction of NR2B, but not NR2A, dramatically increased the number of secondary and tertiary dendritic branches of VSCNs. Whole cell patch-clamp recordings further indicated that the newly formed branches in NR2B-expressing neurons were able to establish functional synapses because the frequency of miniature AMPA-receptor synaptic currents was increased. Using previously described mutants, we also found that disruption of the interaction between NR2B and RasGRF1 dramatically impaired dendritic branch formation in VSCNs. The differential role of the NR2A and NR2B subunits and the requirement for RasGRF1 in regulating branch formation was corroborated in hippocampal cultures. We conclude that the association between NR1NR2B-receptors and RasGRF1 is needed for dendritic branch formation in VSCNs and hippocampal neurons in vitro. The dominated NR2A expression and the limited interactions of this subunit with the signaling protein RasGRF1 may contribute to the restricted dendritic arbor development in the adult CNS.

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Section: Vscns As a Model System To Study Differential Roles Of Nr1nrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Roles of NMDA Receptor Subtypes NR2A and NR2B in Dendritic Branch Development and Requirement of RasGRF1

Sepúlveda¹,

Bustos²,

Inostroza³

et al. 2010

Journal of Neurophysiology

112

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“…Furthermore, AMPA receptor-and NMDA receptor-mediated transmission is required for normal dendritic arbor development (20,33). Because del-CPEB-expressing neurons showed the most severe morphological defects, we tested whether delCPEB expression affects glutamatergic synaptic transmission.…”

Section: Delcpeb Expression Reduces the Strength Of Glutamatergic Synmentioning

confidence: 99%

The RNA binding protein CPEB regulates dendrite morphogenesis and neuronal circuit assembly in vivo

Bestman

Cline

2008

Proc. Natl. Acad. Sci. U.S.A.

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Visual system development requires experience-dependent mechanisms that regulate neuronal structure and function, including dendritic arbor growth, synapse formation, and stabilization. Although RNA binding proteins have been shown to affect some forms of synaptic plasticity in adult animals, their role in the development of neuronal structure and functional circuitry is not clear. Using two-photon time-lapse in vivo imaging and electrophysiology combined with morpholino-mediated knockdown and expression of functional deletion mutants, we demonstrate that the mRNA binding protein, cytoplasmic polyadenylation element binding protein1 (CPEB1), affects experience-dependent neuronal development and circuit formation in the visual system of Xenopus laevis. These data indicate that sensory experience controls circuit development by regulating translational activity of mRNAs.circuit integration ͉ experience-dependent plasticity ͉ in vivo imaging ͉ visual system ͉ whole-cell recording D uring CNS development, neuronal structure, synaptic connections, and circuit functions change in response to sensory input. Although the regulation of mRNA translation and new protein synthesis have been implicated in some forms of neuronal plasticity in adult animals (1, 2), their role in experience-dependent sensory system plasticity has not been addressed (3). In the brain, the translation of many mRNAs is regulated by their association with ribonucleoprotein (RNP) granules, which are composed of core RNA binding proteins, translational machinery, and mRNAs (4). RNA binding proteins package specific mRNAs within RNP granules, regulate their transport into dendrites, and in principle, could temporally and spatially govern their translation in response to synaptic activity (4). Because of these features, mRNA binding proteins are in a unique position to control developmental events through the coordinated translation of a functionally related cohort of mRNAs (5, 6). Indeed, local protein synthesis affords neurons the ability to stabilize changes in synaptic connections and alter neuronal output (7). Recent studies indicate that cytoplasmic polyadenylation element binding protein 1 (CPEB1) is among a handful of RNA binding proteins that regulate dendritic protein synthesis and synaptic plasticity in vitro (8). Although studies in mutant mice implicate CPEB1 in some forms of synaptic and spine plasticity and in memory extinction (9-11), no studies have examined the potential role of CPEB1 in dendritic arbor development, experience-dependent structural plasticity, or the integration of neurons into a functional circuit in an intact animal.CPEB1 (Orb in D. melanogaster) is a member of an evolutionarily conserved family of RNA binding proteins that is expressed in the brain (in vertebrates, CPEB1-4). While all members are defined by the presence of RNA recognition motifs in their carboxy-terminals, CPEB1 is the only member that targets mRNAs containing cytoplasmic polyadenylation elements (CPEs) in their 3Ј untranslated regions (12). Origina...

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“…NMDAR activation accelerates dendritic growth or stabilizes existing arbors (Wu and Cline, 1998). Although the NMDAR subunits GluN2B and GluN2A are both important, neurons overexpressing GluN2B display higher branch dynamics than neurons overexpressing GluN2A (Ewald et al, 2008). Furthermore, a single-cell knockout study has shown that hippocampal pyramidal cells lacking the GluN2B subunit fail to prune extra dendrites, that hippocampal granule and pyramidal cells display a reduced spine density, and that cortical spiny stellates fail to orient dendrites towards the barrels (Espinosa et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Cell class-specific regulation of neocortical dendrite and spine growth by AMPA receptor splice and editing variants

et al. 2011

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SUMMARYGlutamatergic transmission converging on calcium signaling plays a key role in dendritic differentiation. In early development, AMPA receptor (AMPAR) transcripts are extensively spliced and edited to generate subunits that differ in their biophysical properties. Whether these subunits have specific roles in the context of structural differentiation is unclear. We have investigated the role of nine GluA variants and revealed a correlation between the expression of flip variants and the period of major dendritic growth. In interneurons, only GluA1(Q)-flip increased dendritic length and branching. In pyramidal cells, GluA2(Q)-flop, GluA2(Q)-flip, GluA3(Q)-flip and calcium-impermeable GluA2(R)-flip promoted dendritic growth, suggesting that flip variants with slower desensitization kinetics are more important than receptors with elevated calcium permeability. Imaging revealed significantly higher calcium signals in pyramidal cells transfected with GluA2(R)-flip as compared with GluA2(R)-flop, suggesting a contribution of voltage-activated calcium channels. Indeed, dendritic growth induced by GluA2(R)-flip in pyramidal cells was prevented by blocking NMDA receptors (NMDARs) or voltage-gated calcium channels (VGCCs), suggesting that they act downstream of AMPARs. Intriguingly, the action of GluA1(Q)-flip in interneurons was also dependent on NMDARs and VGCCs. Cell class-specific effects were not observed for spine formation, as GluA2(Q)-flip and GluA2(Q)-flop increased spine density in pyramidal cells as well as in interneurons. The results suggest that AMPAR variants expressed early in development are important determinants for activity-dependent dendritic growth in a cell type-specific and cell compartment-specific manner.

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Roles of NR2A and NR2B in the Development of Dendritic Arbor MorphologyIn Vivo

Cited by 91 publications

References 67 publications

Differential Roles of NMDA Receptor Subtypes NR2A and NR2B in Dendritic Branch Development and Requirement of RasGRF1

Differential Roles of NMDA Receptor Subtypes NR2A and NR2B in Dendritic Branch Development and Requirement of RasGRF1

The RNA binding protein CPEB regulates dendrite morphogenesis and neuronal circuit assembly in vivo

Cell class-specific regulation of neocortical dendrite and spine growth by AMPA receptor splice and editing variants

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