CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons

Sara Ricciardi, Federica Ungaro, Melanie Hambrock, Nils Rademacher, Gilda Stefanelli, Dario Brambilla, Alessandro Sessa, Cinzia Magagnotti, Angela Bachi, Elisa Giarda, Chiara Verpelli, Charlotte Kilstrup-Nielsen, Carlo Sala, Vera M. Kalscheuer, Vania Broccoli

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations of the cyclin-dependent kinase-like 5 (CDKL5) and netrin-G1 (NTNG1) genes cause a severe neurodevelopmental disorder with clinical features that are closely related to Rett syndrome, including intellectual disability, early-onset intractable epilepsy and autism. We report here that CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. To exert this role, CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95. Accordingly, phospho-mutant NGL-1 is unable to induce synaptic contacts whereas its phospho-mimetic form binds PSD95 more efficiently and partially rescues the CDKL5-specific spine defects. Interestingly, similarly to rodent neurons, iPSC-derived neurons from patients with CDKL5 mutations exhibit aberrant dendritic spines, thus suggesting a common function of CDKL5 in mice and humans.

Original languageEnglish
Pages (from-to)911-923
Number of pages13
JournalNature Cell Biology
Volume14
Issue number9
DOIs
Publication statusPublished - Sep 2012

ASJC Scopus subject areas

  • Cell Biology

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