Pharmacological Modulation of AMPAR Rescues Intellectual Disability-Like Phenotype in Tm4sf2−/y Mice

Luca Murru, Elena Vezzoli, Anna Longatti, Luisa Ponzoni, Andrea Falqui, Alessandra Folci, Edoardo Moretto, Veronica Bianchi, Daniela Braida, Mariaelvina Sala, Patrizia D’Adamo, Silvia Bassani, Maura Francolini, Maria Passafaro

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Intellectual disability affects 2–3% of the world’s population and typically begins during childhood, causing impairments in social skills and cognitive abilities. Mutations in the TM4SF2 gene, which encodes the TSPAN7 protein, cause a severe form of intellectual disability, and currently, no therapy is able to ameliorate this cognitive impairment. We previously reported that, in cultured neurons, shRNA-mediated down-regulation of TSPAN7 affects AMPAR trafficking by enhancing PICK1–GluA2 interaction, thereby increasing the intracellular retention of AMPAR. Here, we found that loss of TSPAN7 function in mice causes alterations in hippocampal excitatory synapse structure and functionality as well as cognitive impairment. These changes occurred along with alterations in AMPAR expression levels. We also found that interfering with PICK1–GluA2 binding restored synaptic function in Tm4sf2−/y mice. Moreover, potentiation of AMPAR activity via the administration of the ampakine CX516 reverted the neurological phenotype observed in Tm4sf2−/y mice, suggesting that pharmacological modulation of AMPAR may represent a new approach for treating patients affected by TM4SF2 mutations and intellectual disability.
Original languageEnglish (US)
Pages (from-to)5369-5384
Number of pages16
JournalCerebral Cortex
Issue number11
StatePublished - Aug 2 2017

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: Telethon Italy (Grant numbers GGP12097 and GGP17283), Fondazione Mariani, and Fondation Lejeune.


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