Traduction partielle: G.M.
Nature. 2013 Oct 16. doi: 10.1038/nature12618.
SHANK3 et IGF1 restaurent les déficits synaptiques dans les neurones de patients atteints du syndrome de délétion 22q13
Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, Krawisz A, Froehlich W, Bernstein JA, Hallmayer JF, Dolmetsch RE.
Source
Department of Neurobiology, Stanford University, Stanford, California 94305, USA.Abstract
Le syndrome Phelan-McDermid (PMDS) est un trouble neurodéveloppemental complexe, caractérisé par un retard global de développement, une sévère altération de la parole , une déficience intellectuelle, et un risque accru de troubles du spectre autistique (TSA).
PMDS est causé par des délétions hétérozygotes du chromosome 22q13.3.
Among the genes in the deleted region is SHANK3, which encodes a protein in the postsynaptic density (PSD). Rare mutations in SHANK3 have been associated with idiopathic ASDs, non-syndromic intellectual disability, and schizophrenia. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem (iPS) cells from individuals with PMDS and autism and used them to produce functional neurons. We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of mature excitatory synapses that lack SHANK3 but contain PSD95 and N-methyl-d-aspartate (NMDA) receptors with fast deactivation kinetics.
PMDS est causé par des délétions hétérozygotes du chromosome 22q13.3.
Among the genes in the deleted region is SHANK3, which encodes a protein in the postsynaptic density (PSD). Rare mutations in SHANK3 have been associated with idiopathic ASDs, non-syndromic intellectual disability, and schizophrenia. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem (iPS) cells from individuals with PMDS and autism and used them to produce functional neurons. We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of mature excitatory synapses that lack SHANK3 but contain PSD95 and N-methyl-d-aspartate (NMDA) receptors with fast deactivation kinetics.
Nos résultats fournissent la preuve directe d'une perturbation dans le rapport de l'excitation et l'inhibition cellulaire dans les neurones PMDS et fait le point sur une voie moléculaire qui peut être recrutée pour le restaurer.
- PMID: 24132240
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