title: Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome.
abstract: Cotinine is the major metabolite of nicotine and has displayed some capacity for improving cognition in mouse models following chronic administration. We tested if acute cotinine treatment is capable of improving cognition in the mouse model of Fragile X syndrome, Fmr1-/-knockout mice, and if this is related to inhibition by cotinine treatment of glycogen synthase kinase-3β (GSK3β), which is abnormally active in Fmr1-/-mice. Acute cotinine treatment increased the inhibitory serine-phosphorylation of GSK3β and the activating phosphorylation of AKT, which can mediate serine-phosphorylation of GSK3β, in both wild-type and Fmr1-/-mouse hippocampus. Acute cotinine treatment improved cognitive functions of Fmr1-/-mice in coordinate and categorical spatial processing, novel object recognition, and temporal ordering. However, cotinine failed to restore impaired cognition in GSK3β knockin mice, in which a serine9-to-alanine9 mutation blocks the inhibitory serine phosphorylation of GSK3β, causing GSK3β to be hyperactive. These results indicate that acute cotinine treatment effectively repairs impairments of these four cognitive tasks in Fmr1-/-mice, and suggest that this cognition-enhancing effect of cotinine is linked to its induction of inhibitory serine-phosphorylation of GSK3. Taken together, these results show that nicotinic receptor agonists can act as cognitive enhancers in a mouse model of Fragile X syndrome and highlight the potential role of inhibiting GSK3β in mediating the beneficial effects of cotinine on memory.
authors: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.|Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors: Marta
authors: M
authors: Pardo
authors: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.|Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors: Eleonore
authors: E
authors: Beurel
authors: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.|Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors: Richard S
authors: RS
authors: Jope
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003367:Cotinine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013028:Space Perception
chemical_list: D003367:Cotinine; D051860:Fragile X Messenger Ribonucleoprotein 1; D000071679:Glycogen Synthase Kinase 3 beta; D018722:Nicotinic Agonists; D051057:Proto-Oncogene Proteins c-akt; C497684:Fmr1 protein, mouse
keywords: Fragile X syndrome; cotinine; glycogen synthase kinase-3; novel object recognition; spatial memory