Rapamycin improves sociability in the BTBR T+Itpr3/J mouse model of autism spectrum disorders

Abstract

Overactivation of the mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of syndromic forms of autism spectrum disorders (ASDs), such as tuberous sclerosis complex, neurofibromatosis 1, and fragile X syndrome. Administration of mTORC1 (mTOR complex 1) inhibitors (e.g. rapamycin) in syndromic mouse models of ASDs improved behavior, cognition, and neuropathology. However, since only a minority of ASDs are due to the effects of single genes (~10%), there is a need to explore inhibition of mTOR activity in mouse models that may be more relevant to the majority of nonsyndromic presentations, such as the genetically inbred BTBR T+Itpr3tf/J (BTBR) mouse model of ASDs. BTBR mice have social impairment and exhibit increased stereotypic behavior. In prior work, d-cycloserine, a partial glycineB site agonist that targets the N-methyl-d-aspartate (NMDA) receptor, was shown to improve sociability in both Balb/c and BTBR mouse models of ASDs. Importantly, NMDA receptor activation regulates mTOR signaling activity. The current study investigated the ability of rapamycin (10 mg/kg, i.p. × four days), an mTORC1 inhibitor, to improve sociability and stereotypic behavior in BTBR mice. Using a standard paradigm to assess mouse social behavior, rapamycin improved several measures of sociability in the BTBR mouse, suggesting that mTOR overactivation represents a therapeutic target that mediates or contributes to impaired sociability in the BTBR mouse model of ASDs. Interestingly, there was no effect of rapamycin on stereotypic behaviors in this mouse model.

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

“…The main reason for this result might be the low rapamycin dose. In our experiment, 1 mg/kg rapamycin daily was injected to the pups, whereas 6-10 mg/kg rapamycin was usually used to in previous studies (Burket et al, 2014). Furthermore, rapamycin co-treatment ameliorates the symptoms of ASD, suggesting that suppression of mTOR signaling has important therapeutic values in VPA-exposed ASD patients.…”

The mTOR signalling cascade: paving new roads to cure neurological disease

“…For example, knocking out Tsc1 in cerebellar Purkinje cells leads to increased mTOR signalling and autistic-type traits, such as abnormal social interactions, repetitive behaviours, and abnormal vocalizations -all of which could be prevented with rapamycin 84 . Similarly, rapamycin alleviated autistic-type behaviours (deficits in social preferences, abnormalities in ultrasonic vocalizations, repetitive grooming) in another mouse model of autism 85 . One recent study has also implicated mTOR in autism in humans: postmortem analysis of brain tissue from patients with autism spectrum disorders revealed increased density of dendritic spines on layer V pyramidal cells as well as aberrant mTOR activation and reduced autophagy 86 .…”

Rapamycin modulated brain-derived neurotrophic factor and B-cell lymphoma 2 to mitigate autism spectrum disorder in rats

“…Some evidence showed that rapamycin treatment protected neuron viability in stroke, parkinsonism, and early stage Alzheimer-type Tauopathy animal models 9–11. Strikingly, rapamycin supplement mitigated social behavioral abnormality in ASD animal model BTBR mice;12 however, the mechanism was not well revealed.…”