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Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome
Marta Pardo1,2, Eleonore Beurel1,2, Richard S Jope1,2
1Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
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.
Insights
Cotinine, a nicotine metabolite, improved cognitive deficits in a mouse model of Fragile X syndrome. This effect is linked to cotinine
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Cotinine, a major nicotine metabolite, shows potential for cognitive enhancement.
- Fragile X syndrome (FXS) is associated with cognitive impairments and abnormal glycogen synthase kinase-3β (GSK3β) activity.
- The role of acute cotinine administration in FXS cognitive deficits and its mechanism involving GSK3β is not fully understood.
Purpose of the Study:
- To investigate the effects of acute cotinine treatment on cognitive functions in Fmr1-/- mice, a model for FXS.
- To determine if cotinine's cognitive effects are mediated by the inhibition of glycogen synthase kinase-3β (GSK3β).
Main Methods:
- Administered cotinine acutely to wild-type and Fmr1-/- mice.
- Assessed cognitive functions including spatial processing, novel object recognition, and temporal ordering.
- Measured GSK3β phosphorylation and AKT phosphorylation in mouse hippocampus.
Main Results:
- Acute cotinine treatment improved cognitive functions in Fmr1-/- mice across multiple tasks.
- Cotinine increased inhibitory serine-phosphorylation of GSK3β and activating phosphorylation of AKT in the hippocampus.
- Cotinine did not restore cognition in GSK3β knockin mice with a mutation preventing inhibitory phosphorylation.
Conclusions:
- Acute cotinine administration effectively ameliorates cognitive impairments in a mouse model of Fragile X syndrome.
- The cognition-enhancing effects of cotinine are associated with the induction of inhibitory serine-phosphorylation of GSK3β.
- Nicotinic receptor agonists, like cotinine, show promise as cognitive enhancers for FXS, potentially through GSK3β inhibition.
