Pharmacological Modulation of AMPAR Rescues Intellectual Disability-Like Phenotype in Tm4sf2-/yMice

Luca Murru, E Vezzoli, A Longatti, L Ponzoni, A Falqui, A Folci, Edoardo Moretto, V Bianchi, D Braida, M Sala, P D'Adamo, S Bassani, M Francolini, Maria Passafaro

Research output: Contribution to journalArticle

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Abstract

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. © The Author 2017. Published by Oxford University Press.
Original languageEnglish
Pages (from-to)5369-5384
Number of pages16
JournalCerebral Cortex
Volume27
Issue number11
DOIs
Publication statusPublished - 2017

Fingerprint

Intellectual Disability
Pharmacology
Phenotype
Mutation
Aptitude
Synapses
Small Interfering RNA
Down-Regulation
Neurons
Population
Genes
Proteins
Cognitive Dysfunction
Therapeutics
Social Skills
1-(quinoxalin-6-ylcarbonyl)piperidine

Cite this

Murru, L., Vezzoli, E., Longatti, A., Ponzoni, L., Falqui, A., Folci, A., ... Passafaro, M. (2017). Pharmacological Modulation of AMPAR Rescues Intellectual Disability-Like Phenotype in Tm4sf2-/yMice. Cerebral Cortex, 27(11), 5369-5384. https://doi.org/10.1093/cercor/bhx221

Pharmacological Modulation of AMPAR Rescues Intellectual Disability-Like Phenotype in Tm4sf2-/yMice. / Murru, Luca; Vezzoli, E; Longatti, A; Ponzoni, L; Falqui, A; Folci, A; Moretto, Edoardo; Bianchi, V; Braida, D; Sala, M; D'Adamo, P; Bassani, S; Francolini, M; Passafaro, Maria.

In: Cerebral Cortex, Vol. 27, No. 11, 2017, p. 5369-5384.

Research output: Contribution to journalArticle

Murru, L, Vezzoli, E, Longatti, A, Ponzoni, L, Falqui, A, Folci, A, Moretto, E, Bianchi, V, Braida, D, Sala, M, D'Adamo, P, Bassani, S, Francolini, M & Passafaro, M 2017, 'Pharmacological Modulation of AMPAR Rescues Intellectual Disability-Like Phenotype in Tm4sf2-/yMice', Cerebral Cortex, vol. 27, no. 11, pp. 5369-5384. https://doi.org/10.1093/cercor/bhx221
Murru, Luca ; Vezzoli, E ; Longatti, A ; Ponzoni, L ; Falqui, A ; Folci, A ; Moretto, Edoardo ; Bianchi, V ; Braida, D ; Sala, M ; D'Adamo, P ; Bassani, S ; Francolini, M ; Passafaro, Maria. / Pharmacological Modulation of AMPAR Rescues Intellectual Disability-Like Phenotype in Tm4sf2-/yMice. In: Cerebral Cortex. 2017 ; Vol. 27, No. 11. pp. 5369-5384.
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abstract = "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. {\circledC} The Author 2017. Published by Oxford University Press.",
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