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
View: Text | PDF
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

×

Figure 10

Hippocampal insulin-like growth factor-2 (IGF2) levels and behavior after intranasal treatment with IGF2.

Options: View larger image (or click on image) Download as PowerPoint
Hippocampal insulin-like growth factor-2 (IGF2) levels and behavior afte...
We measured hippocampal IGF2 levels to determine if they were lower in Fmr1–/– mice than in WT mice and to test if knocking down GSK3β increased IGF2 levels in Fmr1–/– mice. We also tested if intranasal IGF2 administration was sufficient to ameliorate cognitive impairments in Fmr1–/– mice in novel object recognition, temporal ordering, and coordinate and categorical spatial processing. (A) Hippocampal IGF2 levels were measured after behavioral testing and were lower in Fmr1–/– mice (n = 6) than WT mice (n = 8) after 4 days of treatment with intranasal scrambled siRNA (S) and were increased in Fmr1–/– mice after 4 days of treatment with either of 2 different sequences of GSK3β siRNA B1 (sequence 1; n = 5), or B2 (sequence 2; n = 5) 10 μg/mouse/day (one-way ANOVA: F(3,20) = 7.84, P < 0.01) (**P < 0.01 compared with scrambled siRNA–treated WT mice; *P < 0.05 compared with scrambled siRNA–treated Fmr1–/– mice). n = 24 mice. (B–G) Frmr1–/– mice received intranasal vehicle or IGF2 (0.1 μg/mouse/day) 24 hours and 1 hour prior to behavioral testing. (B) Fmr1–/– mice treated with vehicle displayed a deficit in novel object recognition that was restored by treatment with IGF2 (vehicle: n = 8; t(14) = 2.96, *P < 0.05; IGF2: n = 10; t(18) = 2.92, *P < 0.01). (C) Discrimination index is shown for novel object recognition (t(16) = 2.73, *P < 0.05). (D) Fmr1–/– mice treated with vehicle displayed a deficit in temporal ordering that was improved by treatment with IGF2 (vehicle: n = 9; t(16) = 0.09, n.s.; IGF2: n = 13; t(12) = 2.22, *P < 0.05). 1, first object presented; 3, most recent object presented. (E) Discrimination index is shown for temporal ordering (t(14) = 2.16, *P < 0.05). (F) Coordinate spatial processing was impaired in Fmr1–/– mice (n = 8) and restored after IGF2 treatment (n = 10; t(16) = 4.67, *P < 0.05). (G) Categorical spatial processing was impaired in Fmr1–/– mice (n = 9) and rescued after IGF2 treatment (n = 13; t(14) = 3.82, *P < 0.05). Values are means ± SEM. Each symbol represents the value from an individual mouse.