Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue PLoS Genetics Année : 2021

Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

Thu Lan Nguyen
  • Fonction : Auteur
Javier Flores-Gutiérrez
Giovanni Iacono
  • Fonction : Auteur
Marie-Christine Birling
  • Fonction : Auteur
Valérie Lalanne
  • Fonction : Auteur
Hamid Meziane
Antigoni Manousopoulou
Guillaume Pavlovic
Loïc Lindner
Mohammed Selloum
Tania Sorg
Eugene Yu
Spiros D Garbis
Yann Hérault

Résumé

Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg (Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key postsynaptic proteins implicated in mechanism leading to long-term enhanced synaptic
Fichier principal
Vignette du fichier
Brault et al. 2021.pdf (4.69 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03373419 , version 1 (11-10-2021)

Identifiants

Citer

Véronique Brault, Thu Lan Nguyen, Javier Flores-Gutiérrez, Giovanni Iacono, Marie-Christine Birling, et al.. Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome. PLoS Genetics, 2021, 17 (9), pp.e1009777. ⟨10.1371/journal.pgen.1009777⟩. ⟨hal-03373419⟩
45 Consultations
34 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More