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 4

Cognitive performance of WT and Fmr1–/– mice after intranasal treatment with histone deacetylase-2 (HDAC2) siRNA.

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Cognitive performance of WT and Fmr1–/– mice after intranasal treatment ...
We tested if intranasal administration of siRNA targeting HDAC2 improved novel object recognition, temporal order memory, and coordinate spatial processing in Fmr1–/– mice as it did in GSK3 knockin mice. Mice were treated intranasally daily with scrambled siRNA or HDAC2 siRNA (10 μg/mouse/day) for 3 consecutive days prior to testing and daily throughout the behavioral testing. (A) WT mice spent significantly more time exploring the novel (N) object than the familiar (F) object regardless of treatment (scrambled siRNA: n = 10; t(18) = 8.02, *P < 0.01; HDAC2 siRNA: n = 9; t(16) = 4.32, *P < 0.01). Fmr1–/– mice treated with scrambled siRNA did not display a preference for the novel object (n = 10; t(20) = 3.97, *P < 0.01), but this was restored by treatment with HDAC2 siRNA (n = 11; t(18) = 4.13, *P < 0.01). (B) Discrimination index is shown for novel object recognition (one-way ANOVA: F(3,36) = 13.10, P < 0.01) (**P < 0.05 compared with scrambled siRNA–treated WT mice; *P < 0.05 compared with scrambled siRNA–treated Fmr1–/– mice). (C) WT mice spent significantly more time exploring the first object presented (1) than the most recent object (3) regardless of treatment (scrambled siRNA: n = 10; t(18) = 6.76, *P < 0.01; HDAC2 siRNA: n = 9; t(16) = 7.03, *P < 0.01). Fmr1–/– mice treated with scrambled siRNA displayed a deficit in temporal ordering performance that was partially restored by treatment with HDAC2 siRNA without reaching control levels (scrambled siRNA: n = 10; t(18) = 2.86, P = 0.16; HDAC2 siRNA: n = 10; t(18) = 2.86, P < 0.05). (D) Discrimination index is shown for temporal ordering (one-way ANOVA: F(3,35) = 8.79, P < 0.01) (**P < 0.05 compared with scrambled siRNA–treated WT mice). (E) Coordinate spatial processing was impaired in Fmr1–/– mice and was not rescued after HDAC2 siRNA treatment (one-way ANOVA; n = 9–11; F(3,36) = 15.33, P < 0.01) (**P < 0.05 compared with scrambled siRNA–treated WT mice). (F) Categorical spatial processing was impaired in Fmr1–/– mice but was rescued after HDAC2 siRNA treatment (one-way ANOVA; n = 9–11; F(3,35) = 6.22, P < 0.01) (**P < 0.05 compared with scrambled siRNA–treated WT mice; *P < 0.05 compared with scrambled siRNA–treated Fmr1–/– mice). Values are means ± SEM. Each symbol represents the value from an individual mouse.