Background: Recent evidence suggests that 2-week treatment with the nonpsychotomimetic cannabinoid cannabidivarin (CBDV) could be beneficial towards neurological and social deficits in early symptomatic Mecp2 mutant mice, a model of Rett syndrome (RTT). Aim: To provide further insights into the efficacy of CBDV in Mecp2-null mice we used a lifelong treatment schedule (from 4 to 9 weeks of age) and evaluated its effect on recognition memory and neurological defects in both early and advanced stages of the phenotype progression. Methods: CBDV 0.2, 2, 20, 200 mg/kg/day was administered to Mecp2-null mice from 4 to 9 weeks of age. Cognitive and neurological defects were monitored during the whole treatment schedule. Biochemical analyses were carried out in brain lysates from 9-week-old wildtype and knockout mice to evaluate brainderived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) levels as well as components of the endocannabinoid system. Results: CBDV rescues recognition memory deficits in Mecp2 mutant mice and delays the appearance of neurological defects. At the biochemical level, it normalizes BDNF/IGF1 levels and the defective PI3K/AKT/mTOR pathway in Mecp2 mutant mice at an advanced stage of the disease. Mecp2 deletion 3 upregulates CB1 and CB2 receptor levels in the brain and these changes are restored after CBDV treatment. Conclusions: CBDV administration exerts an enduring rescue of memory deficits in Mecp2 mutant mice, an effect that is associated with the normalization of BDNF, IGF-1 and rpS6 phosphorylation levels as well as CB1 and CB2 receptor expression. CBDV delays neurological defects but this effect is only transient.

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Most of the human population in the western world has access to unlimited calories and leads an increasingly sedentary lifestyle. The propensity to undertake voluntary exercise or indulge in spontaneous physical exercise, which might be termed "exercise salience", is drawing increased scientific attention. Despite its genetic aspects, this complex behaviour is clearly modulated by the environment and influenced by physiological states. Inflammation is often overlooked as one of these conditions even though it is known to induce a state of reduced mobility. Chronic subclinical inflammation is associated with the metabolic syndrome; a largely lifestyle-induced disease which can lead to decreased exercise salience. The result is a vicious cycle that increases oxidative stress and reduces metabolic flexibility and perpetuates the disease state. In contrast, hormetic stimuli can induce an anti-inflammatory phenotype, thereby enhancing exercise salience, leading to greater biological fitness and improved functional longevity. One general consequence of hormesis is upregulation of mitochondrial function and resistance to oxidative stress. Examples of hormetic factors include calorie restriction, extreme environmental temperatures, physical activity and polyphenols. The hormetic modulation of inflammation, and thus, exercise salience, may help to explain the highly heterogeneous expression of voluntary exercise behaviour and therefore body composition phenotypes of humans living in similar obesogenic environments.