Behavioural effects of an intranasal AMPK-targeted treatment for Rett syndrome

Rett syndrome (RTT) is a rare neurological disorder with a monogenic origin, mainly caused by de novo mutations in the methyl-CpG binding protein 2 (MECP2) gene. RTT principally affects females, who develop symptoms at around 1 year of age, and results in impairments at different levels by causing cognitive, motor and social defects, associated with several comorbidities. No cure is currently available. Recently, special interest has been directed toward the involvement of mitochondria dysfunction in the pathogenesis of RTT, as alterations have been described both in the brain and in the periphery. The 5’-adenosine-monophosphate-activated protein kinase (AMPK) is an energy sensor that regulates ATP levels and is essential for the control of mitochondrial function and the maintenance of energy homeostasis. AMPK is also involved in several neurological diseases, characterized by motor and cognitive dysfunction. These features make AMPK a target of potential interest for RTT. The present work evaluated whether the activation of AMPK in the brain can exert beneficial effects on the behavioural alterations of a validated mouse model of RTT (MeCP2-308 heterozygous female mice). To this aim, an 11-day-long intranasal treatment was administrated in fully symptomatic MeCP2-308 mice (12-month-old) with the selective AMPK activator GSK621 (1.5 mg/Kg), which passes the blood-brain barrier. A battery of tests focusing on the most affected behavioural domains in RTT, such as memory and motor skills, was carried out to assess treatment effects thereon. The treatment with GSK621 had a selective effect on recognition memory assessed in the novel object recognition test. No effects on the impaired motor coordination or the general health status were observed. Despite the necessity of follow-up studies to confirm the results obtained, this study lays the foundation for further investigations of the possible involvement of AMPK in the pathogenesis of RTT and the therapeutic potential of its modulation.