title: 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. InFmr1-/-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.affiliation: Department of Psychiatry and Behavioral Sciences.|Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Pardo
authors.affiliation: Department of Psychiatry and Behavioral Sciences.|Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Psychiatry and Behavioral Sciences.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Velmeshev
authors.affiliation: Department of Psychiatry and Behavioral Sciences.
authors.forename: Marco
authors.initials: M
authors.lastname: Magistri
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Eldar-Finkelman
authors.affiliation: Centro de Investigaciones Biologicas-CSIC, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Department of Psychiatry and Behavioral Sciences.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Faghihi
authors.affiliation: Department of Psychiatry and Behavioral Sciences.|Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
authors.affiliation: Department of Psychiatry and Behavioral Sciences.|Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Beurel
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D003072:Cognition Disorders / Q000235:genetics* / Q000523:psychology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics* / Q000523:psychology; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D000071679:Glycogen Synthase Kinase 3 beta; D006655:Histone Deacetylases; D007335:Insulin-Like Growth Factor II; D034741:RNA, Small Interfering; C497684:Fmr1 protein, mouse; C513121:IGF2 protein, mouse; C000605507:Gsk3b protein, mouse