Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice

Marta Pardo, Yuyan Cheng, Dmitry Velmeshev, Marco Magistri, Hagit Eldar-Finkelman, Ana Martinez, Mohammad A Faghihi, Richard S Jope, Eleonore Beurel

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Molecular mechanisms underlying learning and memory remain imprecisely understood, and restorative interventions are lacking. We report that intranasal administration of siRNAs can be used to identify targets important in cognitive processes and to improve genetically impaired learning and memory. In mice modeling the intellectual deficiency of Fragile X syndrome, intranasally administered siRNA targeting glycogen synthase kinase-3β (GSK3β), histone deacetylase-1 (HDAC1), HDAC2, or HDAC3 diminished cognitive impairments. In WT mice, intranasally administered brain-derived neurotrophic factor (BDNF) siRNA or HDAC4 siRNA impaired learning and memory, which was partially due to reduced insulin-like growth factor-2 (IGF2) levels because the BDNF siRNA- or HDAC4 siRNA-induced cognitive impairments were ameliorated by intranasal IGF2 administration. In Fmr1-/- mice, hippocampal IGF2 was deficient, and learning and memory impairments were ameliorated by IGF2 intranasal administration. Therefore intranasal siRNA administration is an effective means to identify mechanisms regulating cognition and to modulate therapeutic targets.

Original languageEnglish (US)
Pages (from-to)e91782
JournalJCI insight
Volume2
Issue number6
DOIs
StatePublished - Mar 23 2017

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Fragile X Syndrome
Intranasal Administration
Somatomedins
Cognition
Small Interfering RNA
Learning
Brain-Derived Neurotrophic Factor
Histone Deacetylase 1
Glycogen Synthase Kinase 3

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Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice. / Pardo, Marta; Cheng, Yuyan; Velmeshev, Dmitry; Magistri, Marco; Eldar-Finkelman, Hagit; Martinez, Ana; Faghihi, Mohammad A; Jope, Richard S; Beurel, Eleonore.

In: JCI insight, Vol. 2, No. 6, 23.03.2017, p. e91782.

Research output: Contribution to journalArticle

Pardo, Marta ; Cheng, Yuyan ; Velmeshev, Dmitry ; Magistri, Marco ; Eldar-Finkelman, Hagit ; Martinez, Ana ; Faghihi, Mohammad A ; Jope, Richard S ; Beurel, Eleonore. / Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice. In: JCI insight. 2017 ; Vol. 2, No. 6. pp. e91782.
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