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 7

Cognitive performance of WT mice after intranasal treatment with siRNA targeting histone deacetylase-4 (HDAC4).

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Cognitive performance of WT mice after intranasal treatment with siRNA t...
We tested if intranasal administration of siRNA targeting HDAC4 altered novel object recognition, temporal order memory, and coordinate and categorical spatial processing in WT mice. WT mice were treated intranasally daily with scrambled siRNA or siRNA targeting HDAC4 (10 μg/mouse/day) for 3 consecutive days prior to testing and daily throughout the behavioral testing. (A) WT mice treated with HDAC4 siRNA displayed a deficit in novel object recognition, spending significantly less time exploring the novel (N) object than the familiar (F) object (scrambled siRNA: n = 8; t(14) = 4.19, *P < 0.01; HDAC4 siRNA: n = 11; t(20) = 2.41, *P < 0.01). (B) Discrimination index is shown for novel object recognition (t(17) = 3.54; *P < 0.01 compared with scrambled siRNA–treated 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 = 8; t(14) = 9.55, *P < 0.01; HDAC4 siRNA: n = 12; t(22) = 4.13, *P < 0.01). (D) Discrimination index is shown for temporal ordering (t(18) = 2.34; *P < 0.05). (E) Coordinate spatial processing was impaired in WT mice after HDAC4 siRNA treatment (n = 8-11; t(17) = 6.26, *P < 0.01). (F) Categorical spatial processing was impaired in WT mice after HDAC4 siRNA treatment (n = 8-12; t(15) = 5.50, *P < 0.01). Values are means ± SEM. Each symbol represents the value from an individual mouse. Student’s t test was used to analyze each behavioral test.