Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex

Abstract

Impairment of reciprocal social interaction is a core symptom of autism spectrum disorder. Genetic disorders frequently accompany autism spectrum disorder, such as tuberous sclerosis complex caused by haploinsufficiency of the TSC1 and TSC2 genes. Accumulating evidence implicates a relationship between autism spectrum disorder and signal transduction that involves tuberous sclerosis complex 1, tuberous sclerosis complex 2 and mammalian target of rapamycin. Here we show behavioural abnormalities relevant to autism spectrum disorder and their recovery by the mammalian target of rapamycin inhibitor rapamycin in mouse models of tuberous sclerosis complex. In Tsc2+/− mice, we find enhanced transcription of multiple genes involved in mammalian target of rapamycin signalling, which is dependent on activated mammalian target of rapamycin signalling with a minimal influence of Akt. The findings indicate a crucial role of mammalian target of rapamycin signalling in deficient social behaviour in mouse models of tuberous sclerosis complex, supporting the notion that mammalian target of rapamycin inhibitors may be useful for the pharmacological treatment of autism spectrum disorder associated with tuberous sclerosis complex and other conditions that result from dysregulated mammalian target of rapamycin signalling.

Everolimus improves behavioral deficits in a patient with autism associated with tuberous sclerosis: a case report

“…These cognitive abnormalities emerged in the absence of neuropathology and seizures (Ehninger et al 2008(Ehninger et al , 2009. A recent study by Sato et al (2012) in TSC mutant adult mice found that impaired social behavior also reversed by mTOR inhibitor treatment, which associated with mTOR inhibition at the molecular level. Others have also provided evidence that autistic-like behavior can be prevented with mTOR treatment in mouse models of TSC (Tsai et al, 2012;Talos et al, 2012;Reith et al 2013).…”

Enhanced synapse remodelling as a common phenotype in mouse models of autism

“…Rett syndrome, fragile X syndrome and tuberous sclerosis complex exhibit comorbidity with ASDs, and their corresponding mouse models were established and extensively studied [16][17][18][19] . Rescue experiments using these syndromic ASD mouse models successfully identified key molecular pathways involved in the pathology of neural circuits and behavioural deficits [9][10][11][20][21][22] . However, most ASD cases are non-syndromic, and recent genetic studies of non-syndromic ASDs identified a large number of candidates with rare genetic variants 6,7 .…”

Targeted therapy for tuberous sclerosis complex

“…Эксперимен-тальные модели туберозного склероза убедительно демонстрируют, что нарушения mTOR играют клю-чевую роль в формировании социального поведения и обучения [14]. Короткий курс рапамицина не толь-ко восстанавливал синаптическую пластичность, но и уменьшал нарушения поведения у эксперимен-тальных животных [15].…”