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 8

Intranasal treatment with insulin-like growth factor-2 (IGF2) improves impaired cognition caused by intranasal histone deacetylase-4 (HDAC4) siRNA administration.

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Intranasal treatment with insulin-like growth factor-2 (IGF2) improves i...
We tested if intranasal administration of IGF2 altered the performance of HDAC4 siRNA–treated WT mice in novel object recognition, temporal order memory, and coordinate and categorical spatial processing to determine if deficient IGF2 contributed to impairments induced by knocking down HDAC4. WT mice were treated intranasally with HDAC4 siRNA (10 μg/mouse/day) for 3 days followed by vehicle or IGF2 (0.1 μg/mouse/day) 24 hours and 1 hour prior to behavioral testing. (A) HDAC4 siRNA plus vehicle–treated mice displayed a deficit in novel object recognition that was restored by treatment with IGF2 (vehicle: n = 9; t(16) = 3.74, *P < 0.01; IGF2: n = 9; t(16) = 5.31, *P < 0.01). (B) Discrimination index is shown for novel object recognition (t(16) = 4.59, *P < 0.01). (C) Mice treated with HDAC4 siRNA plus vehicle spent significantly more time exploring the first object presented (1) than the most recent object (3) (n = 8; t(14) = 3.65, *P < 0.01), and IGF2 treatment did not alter temporal ordering performance (n = 8; t(14) = 3.00, *P < 0.01). (D) Discrimination index in temporal ordering was not different between vehicle- and IGF2-treated mice (t(14) = 0.67, n.s.). (E) Mice treated with HDAC4 siRNA plus vehicle (n = 9) displayed impaired coordinate spatial processing that was improved by treatment with IGF2 (n = 9; t(16) = 4.16, *P < 0.01). (F) Mice treated with HDAC4 siRNA plus vehicle (n = 9) displayed impaired categorical spatial processing that was restored by treatment with IGF2 (n = 9; t(16) = 6.14, *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.