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
• Journal: JCI insight (JCI Insight) Vol. 2 Issue 6 Pg. e91782 (03 23 2017) ISSN: 2379-3708 [Electronic] United States
• PMID: 28352664 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fmr1 protein, mouse
• IGF2 protein, mouse
• RNA, Small Interfering
• Fragile X Mental Retardation Protein
• Insulin-Like Growth Factor II
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Histone Deacetylases

Topics

• Administration, Intranasal
• Animals
• Cognition Disorders (genetics, psychology)
• Fragile X Mental Retardation Protein (genetics)
• Fragile X Syndrome (genetics, psychology)
• Glycogen Synthase Kinase 3 beta (genetics)
• Histone Deacetylases (genetics)
• Insulin-Like Growth Factor II (genetics)
• Mice
• Mice, Knockout
• RNA, Small Interfering (administration & dosage)