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 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 effects of cotinine on memory.

Disparate Effects of Lithium and a GSK-3 Inhibitor on Neuronal Oscillatory Activity in Prefrontal Cortex and Hippocampus

“…More recently, developmental inhibition of GSK-3 was shown to alleviate spatial memory deficiencies in a mouse model of schizophrenia predisposition ( Tamura et al, 2016 ) indicative of a direct link between GSK-3 and the development of processes critical to aberrant cognitive functioning in this disorder. In line with these findings GSK-3 has been shown to be involved in mediating reductions in cognitive performance associated with diabetes mellitus ( King et al, 2013 ; Wang and Zhao, 2016 ), Fragile-X syndrome ( Guo et al, 2012 ; Franklin et al, 2014 ; Pardo et al, 2017 ), and human immunodeficiency virus ( Ances et al, 2008 ), and in a model of traumatic brain injury improvements in spatial memory induced by valproate were associated with inhibition of GSK-3 in hippocampus ( Dash et al, 2010 ).…”

“…Preclinical studies in animal models of disease have provided promising evidence of cognitive improvement as a result of treatment with GSK-3 inhibitors, with beneficial effects of GSK-3 inhibition, either by lithium or selective inhibitors, having been demonstrated in model systems of schizophrenia ( Beaulieu et al, 2004 ; Chan et al, 2012 ; Lipina et al, 2013 ; Maksimovic et al, 2014 ), Fragile-X syndrome ( Yuskaitis et al, 2010 ; Guo et al, 2012 ; Franklin et al, 2014 ; Pardo et al, 2017 ) as well as traumatic brain injury ( Yu et al, 2012a , b ). In addition, the large number of reports that have focused on AD, as a result of the known role of GSK-3 in AD neuropathology, are also positive showing significant improvements not only in cognitive performance but also in AD-related pathologies ( Hu et al, 2009 ; Sereno et al, 2009 ; Gong et al, 2011 ; Onishi et al, 2011 ; Zhang et al, 2011 ; Avrahami et al, 2013 ; Noh et al, 2013 ; Nunes et al, 2015 ).…”

Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery

“…109 Acute administration of the nicotine metabolite cotinine has also been shown to attenuate impairments of a spatial object recognition task in a mouse model of Fragile X syndrome. 110 In the case of nicotine, the effects can shift from enhancement of performance to impairments as administration changes from acute to chronic and during withdrawal, however. 109 These effects were specific for spatial object recognition (as opposed to NOR), which led the authors to hypothesize that this could be because of differing underlying neural substrates involved performance of the two tasks.…”

Explorations and perspectives on the neurobiological bases of autism spectrum disorder

“…Of course, the relevance of the work is only as good as the model system, and there has been much ringing of hands with regard to the existing animal models for autism. The animal model approach tends to work well in monogenic diseases like Rett (Watase & Zoghbi, ; Ladas et al ., ) or Fragile X syndrome (Richter et al ., ; Pardo et al ., ), where the causal mutations giving rise to the human condition are known, can be engineered in the mouse model, and where the human disease phenotype is relatively well recapitulated in the animal. This approach, however, is considerably more complicated in a condition as heterogeneous as ASD, where diagnosis is based purely on clinical symptoms, and most everyone agrees that in the vast majority of cases, it represents a constellation of related conditions of mixed genotypic background (C Yuen et al ., ; Vorstman et al ., ).…”