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 6

Cognitive performance of WT and glycogen synthase kinase-3 (GSK3) knockin mice after intranasal treatment with histone deacetylase-3 (HDAC3) siRNA.

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Cognitive performance of WT and glycogen synthase kinase-3 (GSK3) knocki...
We tested if intranasal administration of siRNA targeting HDAC3 improved novel object recognition, temporal order memory, and coordinate spatial processing that are impaired in GSK3 knockin (KI) mice, which recapitulate these impairments of Fmr1–/– mice due to the hyperactive GSK3. Mice were treated intranasally with scrambled siRNA or HDAC3 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 = 9; t(16) = 7.94 *P < 0.01; HDAC3 siRNA: n = 10; t(18) = 6.55, *P < 0.01 compared with % time spent exploring familiar object). GSK3 KI mice treated with scrambled siRNA displayed a deficit in novel object recognition that was improved by treatment with HDAC3 siRNA (scrambled siRNA: n = 8; t(14) = 0.58, n.s.; HDAC3 siRNA: n = 8; t(14) = 3.43, *P < 0.01 compared with % time spent exploring familiar object). (B) Discrimination index is shown for novel object recognition (one-way ANOVA: F(3,34) = 6.65, P < 0.01) (**P < 0.01 compared with scrambled siRNA–treated WT mice). (C) WT mice spent significantly more time exploring the first object (1) presented than the most recent object (3) regardless of treatment (scrambled siRNA: n = 10; t(18) = 7.43, *P < 0.01; HDAC3 siRNA: n = 10; t(18) = 7.59, *P < 0.01 compared with % time spent exploring the first object). GSK3 KI mice treated with scrambled siRNA displayed a deficit in temporal ordering performance that was rescued by treatment with HDAC3 siRNA (scrambled siRNA: n = 11; t(20) = 4.65, *P < 0.01; HDAC3 siRNA: n = 7; t(12) = 7.40, *P < 0.01 compared with % time spent exploring first object). (D) Discrimination index is shown for temporal ordering (one-way ANOVA; F(3,37) = 20.42; P < 0.01) (**P < 0.01 compared with scrambled siRNA–treated WT mice; *P < 0.01 compared with scrambled siRNA–treated KI mice). (E) Coordinate spatial processing was impaired in GSK3 KI mice, and this was not altered by HDAC3 siRNA treatment (one-way ANOVA: n = 8-12; F(3,39) = 12.16, P < 0.01) (**P < 0.01 compared with scrambled siRNA–treated WT mice). Values are means ± SEM. Each symbol represents the value from an individual mouse.