---
_id: '10301'
abstract:
- lang: eng
  text: De novo protein synthesis is required for synapse modifications underlying
    stable memory encoding. Yet neurons are highly compartmentalized cells and how
    protein synthesis can be regulated at the synapse level is unknown. Here, we characterize
    neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic
    target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to
    mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A
    subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR
    complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR
    activation and restricts the mTOR-dependent translation of specific activity-regulated
    mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent
    protein synthesis, and facilitates the consolidation of associative and spatial
    memories in mice. The memory enhancement becomes evident with light or spaced
    training, can be achieved by selectively deleting GluN3A from excitatory neurons
    during adulthood, and does not compromise other aspects of cognition such as memory
    flexibility or extinction. Our findings provide mechanistic insight into synaptic
    translational control and reveal a potentially selective target for cognitive
    enhancement.
acknowledgement: We thank Stuart Lipton and Nobuki Nakanishi for providing the Grin3a
  knockout mice, Beverly Davidson for the AAV-caRheb, Jose Esteban for help with behavioral
  and biochemical experiments, and Noelia Campillo, Rebeca Martínez-Turrillas, and
  Ana Navarro for expert technical help. Work was funded by the UTE project CIMA;
  fellowships from the Fundación Tatiana Pérez de Guzmán el Bueno, FEBS, and IBRO
  (to M.J.C.D.), Generalitat Valenciana (to O.E.-Z.), Juan de la Cierva (to L.G.R.),
  FPI-MINECO (to E.R.V., to S.N.) and Intertalentum postdoctoral program (to V.B.);
  ANR (GluBrain3A) and ERC Advanced Grants (#693021) (to P.P.); Ramón y Cajal program
  RYC2014-15784, RETOS-MINECO SAF2016-76565-R, ERANET-Neuron JTC 2019 ISCIII AC19/00077
  FEDER funds (to R.A.); RETOS-MINECO SAF2017-87928-R (to A.B.); an NIH grant (NS76637)
  and UTHSC College of Medicine funds (to S.J.T.); and NARSAD Independent Investigator
  Award and grants from the MINECO (CSD2008-00005, SAF2013-48983R, SAF2016-80895-R),
  Generalitat Valenciana (PROMETEO 2019/020)(to I.P.O.) and Severo-Ochoa Excellence
  Awards (SEV-2013-0317, SEV-2017-0723).
article_number: e71575
article_processing_charge: No
article_type: original
author:
- first_name: María J
  full_name: Conde-Dusman, María J
  last_name: Conde-Dusman
- first_name: Partha N
  full_name: Dey, Partha N
  last_name: Dey
- first_name: Óscar
  full_name: Elía-Zudaire, Óscar
  last_name: Elía-Zudaire
- first_name: Luis E
  full_name: Garcia Rabaneda, Luis E
  id: 33D1B084-F248-11E8-B48F-1D18A9856A87
  last_name: Garcia Rabaneda
- first_name: Carmen
  full_name: García-Lira, Carmen
  last_name: García-Lira
- first_name: Teddy
  full_name: Grand, Teddy
  last_name: Grand
- first_name: Victor
  full_name: Briz, Victor
  last_name: Briz
- first_name: Eric R
  full_name: Velasco, Eric R
  last_name: Velasco
- first_name: Raül
  full_name: Andero Galí, Raül
  last_name: Andero Galí
- first_name: Sergio
  full_name: Niñerola, Sergio
  last_name: Niñerola
- first_name: Angel
  full_name: Barco, Angel
  last_name: Barco
- first_name: Pierre
  full_name: Paoletti, Pierre
  last_name: Paoletti
- first_name: John F
  full_name: Wesseling, John F
  last_name: Wesseling
- first_name: Fabrizio
  full_name: Gardoni, Fabrizio
  last_name: Gardoni
- first_name: Steven J
  full_name: Tavalin, Steven J
  last_name: Tavalin
- first_name: Isabel
  full_name: Perez-Otaño, Isabel
  last_name: Perez-Otaño
citation:
  ama: Conde-Dusman MJ, Dey PN, Elía-Zudaire Ó, et al. Control of protein synthesis
    and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly.
    <i>eLife</i>. 2021;10. doi:<a href="https://doi.org/10.7554/elife.71575">10.7554/elife.71575</a>
  apa: Conde-Dusman, M. J., Dey, P. N., Elía-Zudaire, Ó., Garcia Rabaneda, L. E.,
    García-Lira, C., Grand, T., … Perez-Otaño, I. (2021). Control of protein synthesis
    and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly.
    <i>ELife</i>. eLife Sciences Publications. <a href="https://doi.org/10.7554/elife.71575">https://doi.org/10.7554/elife.71575</a>
  chicago: Conde-Dusman, María J, Partha N Dey, Óscar Elía-Zudaire, Luis E Garcia
    Rabaneda, Carmen García-Lira, Teddy Grand, Victor Briz, et al. “Control of Protein
    Synthesis and Memory by GluN3A-NMDA Receptors through Inhibition of GIT1/MTORC1
    Assembly.” <i>ELife</i>. eLife Sciences Publications, 2021. <a href="https://doi.org/10.7554/elife.71575">https://doi.org/10.7554/elife.71575</a>.
  ieee: M. J. Conde-Dusman <i>et al.</i>, “Control of protein synthesis and memory
    by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly,” <i>eLife</i>,
    vol. 10. eLife Sciences Publications, 2021.
  ista: Conde-Dusman MJ, Dey PN, Elía-Zudaire Ó, Garcia Rabaneda LE, García-Lira C,
    Grand T, Briz V, Velasco ER, Andero Galí R, Niñerola S, Barco A, Paoletti P, Wesseling
    JF, Gardoni F, Tavalin SJ, Perez-Otaño I. 2021. Control of protein synthesis and
    memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. eLife.
    10, e71575.
  mla: Conde-Dusman, María J., et al. “Control of Protein Synthesis and Memory by
    GluN3A-NMDA Receptors through Inhibition of GIT1/MTORC1 Assembly.” <i>ELife</i>,
    vol. 10, e71575, eLife Sciences Publications, 2021, doi:<a href="https://doi.org/10.7554/elife.71575">10.7554/elife.71575</a>.
  short: M.J. Conde-Dusman, P.N. Dey, Ó. Elía-Zudaire, L.E. Garcia Rabaneda, C. García-Lira,
    T. Grand, V. Briz, E.R. Velasco, R. Andero Galí, S. Niñerola, A. Barco, P. Paoletti,
    J.F. Wesseling, F. Gardoni, S.J. Tavalin, I. Perez-Otaño, ELife 10 (2021).
date_created: 2021-11-18T06:59:45Z
date_published: 2021-11-17T00:00:00Z
date_updated: 2023-08-14T11:50:50Z
day: '17'
ddc:
- '570'
department:
- _id: GaNo
doi: 10.7554/elife.71575
external_id:
  isi:
  - '000720945900001'
file:
- access_level: open_access
  checksum: 59318e9e41507cec83c2f4070e6ad540
  content_type: application/pdf
  creator: lgarciar
  date_created: 2021-11-18T07:02:02Z
  date_updated: 2021-11-18T07:02:02Z
  file_id: '10302'
  file_name: elife-71575-v1.pdf
  file_size: 2477302
  relation: main_file
  success: 1
file_date_updated: 2021-11-18T07:02:02Z
has_accepted_license: '1'
intvolume: '        10'
isi: 1
keyword:
- general immunology and microbiology
- general biochemistry
- genetics and molecular biology
- general medicine
- general neuroscience
language:
- iso: eng
month: '11'
oa: 1
oa_version: Published Version
publication: eLife
publication_identifier:
  issn:
  - 2050-084X
publication_status: published
publisher: eLife Sciences Publications
quality_controlled: '1'
status: public
title: Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition
  of GIT1/mTORC1 assembly
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 10
year: '2021'
...
---
_id: '7957'
abstract:
- lang: eng
  text: "Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain
    development and function and are characterized by wide genetic and clinical variability.
    In this review, we discuss the multiple factors that influence the clinical presentation
    of NDDs, with particular attention to gene vulnerability, mutational load, and
    the two-hit model. Despite the complex architecture of\r\nmutational events associated
    with NDDs, the various proteins involved appear to converge on common pathways,
    such as synaptic plasticity/function, chromatin remodelers and the mammalian target
    of rapamycin (mTOR) pathway. A thorough understanding of the mechanisms behind
    these pathways will hopefully lead to the identification of candidates that could
    be targeted for treatment approaches."
acknowledgement: We wish to thank Jasmin Morandell for generously sharing Figure 2.
  This work was supported by the European Research Council Starting Grant (grant 715508
  ) to G.N.
article_processing_charge: No
article_type: original
author:
- first_name: Ilaria
  full_name: Parenti, Ilaria
  id: D93538B0-5B71-11E9-AC62-02EBE5697425
  last_name: Parenti
- first_name: Luis E
  full_name: Garcia Rabaneda, Luis E
  id: 33D1B084-F248-11E8-B48F-1D18A9856A87
  last_name: Garcia Rabaneda
- first_name: Hanna
  full_name: Schön, Hanna
  id: C8E17EDC-D7AA-11E9-B7B7-45ECE5697425
  last_name: Schön
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
citation:
  ama: 'Parenti I, Garcia Rabaneda LE, Schön H, Novarino G. Neurodevelopmental disorders:
    From genetics to functional pathways. <i>Trends in Neurosciences</i>. 2020;43(8):608-621.
    doi:<a href="https://doi.org/10.1016/j.tins.2020.05.004">10.1016/j.tins.2020.05.004</a>'
  apa: 'Parenti, I., Garcia Rabaneda, L. E., Schön, H., &#38; Novarino, G. (2020).
    Neurodevelopmental disorders: From genetics to functional pathways. <i>Trends
    in Neurosciences</i>. Elsevier. <a href="https://doi.org/10.1016/j.tins.2020.05.004">https://doi.org/10.1016/j.tins.2020.05.004</a>'
  chicago: 'Parenti, Ilaria, Luis E Garcia Rabaneda, Hanna Schön, and Gaia Novarino.
    “Neurodevelopmental Disorders: From Genetics to Functional Pathways.” <i>Trends
    in Neurosciences</i>. Elsevier, 2020. <a href="https://doi.org/10.1016/j.tins.2020.05.004">https://doi.org/10.1016/j.tins.2020.05.004</a>.'
  ieee: 'I. Parenti, L. E. Garcia Rabaneda, H. Schön, and G. Novarino, “Neurodevelopmental
    disorders: From genetics to functional pathways,” <i>Trends in Neurosciences</i>,
    vol. 43, no. 8. Elsevier, pp. 608–621, 2020.'
  ista: 'Parenti I, Garcia Rabaneda LE, Schön H, Novarino G. 2020. Neurodevelopmental
    disorders: From genetics to functional pathways. Trends in Neurosciences. 43(8),
    608–621.'
  mla: 'Parenti, Ilaria, et al. “Neurodevelopmental Disorders: From Genetics to Functional
    Pathways.” <i>Trends in Neurosciences</i>, vol. 43, no. 8, Elsevier, 2020, pp.
    608–21, doi:<a href="https://doi.org/10.1016/j.tins.2020.05.004">10.1016/j.tins.2020.05.004</a>.'
  short: I. Parenti, L.E. Garcia Rabaneda, H. Schön, G. Novarino, Trends in Neurosciences
    43 (2020) 608–621.
date_created: 2020-06-14T22:00:49Z
date_published: 2020-08-01T00:00:00Z
date_updated: 2023-08-21T08:25:31Z
day: '01'
ddc:
- '570'
department:
- _id: GaNo
doi: 10.1016/j.tins.2020.05.004
ec_funded: 1
external_id:
  isi:
  - '000553090600008'
  pmid:
  - '32507511'
file:
- access_level: open_access
  checksum: 67db0251b1d415ae59005f876fcf9e34
  content_type: application/pdf
  creator: dernst
  date_created: 2020-11-25T09:43:40Z
  date_updated: 2020-11-25T09:43:40Z
  file_id: '8805'
  file_name: 2020_TrendsNeuroscience_Parenti.pdf
  file_size: 1439550
  relation: main_file
  success: 1
file_date_updated: 2020-11-25T09:43:40Z
has_accepted_license: '1'
intvolume: '        43'
isi: 1
issue: '8'
language:
- iso: eng
month: '08'
oa: 1
oa_version: Published Version
page: 608-621
pmid: 1
project:
- _id: 25444568-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '715508'
  name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
    and in vitro Models
publication: Trends in Neurosciences
publication_identifier:
  eissn:
  - 1878108X
  issn:
  - '01662236'
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'Neurodevelopmental disorders: From genetics to functional pathways'
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 43
year: '2020'
...