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

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

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.

Authors

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

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Figure 11

Cognitive performance of TDZD-8–treated Fmr1–/– mice after intranasal administration of insulin-like growth factor-2 (IGF2) siRNA.

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Cognitive performance of TDZD-8–treated Fmr1–/– mice after intranasal ad...
We tested if intranasal administration of IGF2 siRNA impaired the cognition-repairing effects of the specific GSK3 inhibitor TDZD-8 in Fmr1–/– mice in novel object recognition, temporal ordering, and coordinate and categorical spatial processing. Mice were treated intranasally with scrambled siRNA or IGF2 siRNA (10 μg/mouse/day) administered 3 consecutive days prior to testing and daily throughout the behavioral testing. TDZD-8 (5 mg/kg; i.p.) or vehicle was administered 1 hour prior to behavioral testing. (A) Fmr1–/– mice treated with scrambled siRNA displayed a deficit in novel object recognition that was rescued by treatment with TDZD-8 (vehicle: n = 10; t(18) = 3.45, *P < 0.01; TDZD-8: n = 9; t(16) = 3.12, *P < 0.01). Treatment with IGF2 siRNA diminished the improvement in novel object recognition induced by treatment with TDZD-8 (n = 7; t(12) = 0.43, n.s.). (B) Discrimination index is shown for novel object recognition (one-way ANOVA: F(2,25) = 6.41, P < 0.01) (*P < 0.01 compared with scrambled siRNA– and vehicle-treated Fmr1–/– mice). (C) Fmr1–/– mice treated with scrambled siRNA displayed a deficit in temporal ordering that was rescued by treatment with TDZD-8 (scrambled siRNA: n = 10; t(18) = 2.67, *P < 0.05; TDZD-8: n = 9; t(16) = 3.09, *P < 0.01). 1, first object presented; 3, most recent object presented. IGF2 siRNA diminished the improvement in temporal ordering induced by treatment with TDZD-8 (n = 7; t(12) = 0.90, n.s.). (D) Discrimination index is shown for temporal ordering (one-way ANOVA: F(2,25) = 4.68, P < 0.05) (*P < 0.05 compared with scrambled siRNA- and vehicle-treated Fmr1–/– mice). (E) Fmr1–/– mice displayed impaired coordinate spatial processing (n = 10) that was rescued by treatment with TDZD-8 (n = 9), and the TDZD-8–induced improvements were blocked by IGF2 siRNA (n = 7) treatment (F(2,25) = 11.56, P < 0.01) (*P < 0.01 compared with scrambled siRNA– and vehicle-treated Fmr1–/– mice). (F) Fmr1–/– mice displayed impaired categorical spatial processing (n = 10) that was restored by treatment with TDZD-8 (n = 9), and the TDZD-8–induced improvements were blocked by IGF2 siRNA (n = 7) treatment (one-way ANOVA: F(2,25) = 24.39, P < 0.01) (*P < 0.01 compared with scrambled siRNA– and vehicle-treated Fmr1–/– mice). Values are means ± SEM. Each symbol represents the value from an individual mouse.