The Reversal of Social Deficits in Autism: rapamycin to the rescue | Review by Umang Khan
The Reversal of Social Deficits in Autism: rapamycin to the rescue.
Neuroscience, Human Biology Program, University of Toronto, Toronto ON, M5S 3J6
ABSTRACT: This paper studies the process of synaptic pruning in individuals with Autism Spectrum Disorder (ASD). The process of synaptic pruning is hindered due to over activation of mammalian target of rapamycin (mTOR) and lack of regulation by its dependent autophagy. This hindrance prevents correct synaptic pruning to occur from childhood to adolescence thereby keeping a great number of synapses in ASD individuals. This could be a reason for the social deficits in ASD as excess synapses leads to overwhelming sensations resulting in withdrawn behaviour. However, rapamycin, which is an mTOR inhibitor, can remove this defect and allow synaptic pruning to take place. This could take away the social deficits involved in ASD.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder involving social impairments such as communication difficulties as well as lack of interest in other people’s emotions or actions (Steyn, & Couteur, 2003). ASD affects 1 in 68 children where boys are 4.5 times more likely to develop it than girls (Christensen et al., 2016). Studies have shown that individuals with ASD have larger brain volume (Hardan, Minshew, Mallikarjuhn, & Keshavan, 2001). There is substantial increase in brain size during the first 4 years of life (Bourgeron, 2009) particularly the fronto-occipital head circumference. The reason for this brain size is unknown however, a proposed reason is that ASD individuals have greater synaptic density that may lead to greater brain size. Therefore, this paper provides insight into how synaptic pruning defects lead to greater brain density and a potential drug that could reverse these effects.
Typical children show rich synaptic density in early childhood however, this decreases substantially once they have reached adolescence (Tang et al., 2014). This is due to synaptic pruning which allows for brain maturation. However, children with ASD do not show this decrease in synaptic density indicating that deficits are present in the synaptic pruning mechanism.
In this study, the neurobiological processes of synaptic pruning are examined, particularly, the mammalian target of rapamycin (mTOR) pathway. mTOR signalling has been reported to be over activated in ASD individuals (Bourgeron, 2009) due to haploinsufficiency of tuberous sclerosis complex 1 and 2 (Tsc1 and Tsc2) (Sato et al., 2012). This complex involves an autosomal dominant disorder due to mutations in Tsc1 or Tsc2 resulting in over activation of mTOR signalling. Normally, the tuberous sclerosis complexes inhibit Rheb which in turn inhibits mTOR signalling however, the mutation prevents inhibition of Rheb thereby leading to excess mTOR activity (Burket, Benson, Tang, & Deutsch, 2014).
Furthermore, activation of the mTOR pathway results in the production of protein synthesis which is usually evened out with protein degradation to maintain homeostasis. In order for this to occur, autophagosomes have to be formed to remove debris – resulting from degradation – from the cytoplasm and transport it to lysosomes. However, in this case, excessive mTOR signalling results in a surplus of protein synthesis such that autophagosome formation is brought to a halt ultimately preventing autophagy (Tang et al., 2014). This lack of autophagy is the underlying cause of synaptic pruning deficits such that ASD individuals show higher synaptic density in areas such as the Brodmann Area 21 (BA21) than control individuals.
The study looks to correct such defects by the use of rapamycin. Rapamycin is known to inhibit activation of mTOR signalling (Sato et al., 2012). The drug was administered to rats with Tsc2 mutations. Results indicate the rectification of synaptic pruning defects in Tsc2 mutant mice whereas it had no effect on wildtype mice. Therefore, rapamycin may be a solution for autophagy defects, synaptic pruning defects and essentially the social defects in ASD.
The study finds that autophagy is stopped due to excess mTOR signalling. This is seen in Western Blot results indicating lower levels of LC3-II (marker for autophagosomes) present in ASD individuals. Furthermore, Western Blot tests reveal high levels of phospho-S6 (p-S6), a marker for mTOR activity thereby indicating high levels of mTOR activity are taking place in the autistic brain. Rapamycin was tested in mice with Tsc2 mutations showing positive effects that led to decreased mTOR activity. Tsc1 and Tsc2 are genes that inhibit Rheb which is responsible for over activation of mTOR. However, mutations in these genes allow Rheb activity to take place which in turn leads to increased mTOR activity. This interrupts the synaptic pruning process. Furthermore, DiOlistic labelling was used to examine synaptic density in primary auditory cortex and secondary somatosensory cortex in mutant mice as well as wildtype mice. A period of significant synaptic pruning was found in wildtype mice between ages P20 to P30 whereas mutant mice did not show this effect. Due to this, social interaction in mutant mice was measured using the three-chamber test verifying their social deficits. In order to eliminate synaptic pruning defects, rapamycin was administered intraperitoneally in both mutant mice and wildtype mice. Results showed sufficient levels of LC3-II in mutant mice indicating formation of autophagosomes are present however, no effects
were seen in wildtype mice. Therefore, synaptic pruning deficits were corrected in mutant mice.
mTOR activity has been shown to affect synaptic pruning negatively due to lack of autophagy. Therefore, ASD individuals show greater synaptic density through adolescence even though this is not the case in typical individuals. However, rapamycin has been proposed to reverse such effects as tested with Tsc2 mutant mice who showed less social deficits after rapamycin administration. To conclude, rapamycin may be a potential treatment for the social defects presented by ASD individuals.
This is important to consider as previous theories have stated that ASD individuals exhibit abnormalities in sensory perception such that they perceive an overwhelming amount of sensory information (Markram, Rinaldi, & Markram, 2007). This could be a cause for their social withdrawal and may be due to the increased synaptic density. Furthermore, it has been found that 20 % to 60% of ASD individuals are also patients with tuber sclerosis indicating that Tsc2 mutations may be a genetic factor involved in ASD social symptoms (Kaeberlein, 2013).
Although rapamycin seems like an effective treatment, the results have yet to be replicated in human studies. Mice have shown insulin resistance when treated with rapamycin consistently (Kaeberlein, 2013). Therefore, better understanding of rapamycin and its effects needs to be developed as the focus in this study has only been on the brain without any consideration of other pathways in the body such as metabolism.
It is also important to note that not all ASD individuals show the same symptoms (Steyn, & Couteur, 2003). As the name indicates, ASD is a spectrum. Therefore, it is yet to be understood whether there is also a spectrum of genes that are responsible for this disorder or a single gene responsible for the entire spectrum (Markram, & Markram, 2010). Tsc2 is most probably one of many mutations that lead to ASD symptoms therefore, it is important to gain greater insight into the genetics of ASD to decide whether a drug like rapamycin can be used effectively.
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Burket, J., Benson, A., Tang, A., & Deutsch, S. (2014). Rapamycin improves sociability in the BTBR T+Itpr3tf/J mouse model of autism spectrum disorders. Brain Research Bulletin, 100, 70-75. http://dx.doi.org/10.1016/j.brainresbull.2013.11.005
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Sato, A., Kasai, S., Kobayashi, T., Takamatsu, Y., Hino, O., Ikeda, K., & Mizuguchi, M. (2012). Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nature Communications, 3, 1292. http://dx.doi.org/10.1038/ncomms2295
Steyn, B., & Couteur, A. (2003). Understanding autism spectrum disorders. Current Paediatrics, 13(4), 274-278. http://dx.doi.org/10.1016/s0957-5839(03)00049-6
Tang, G., Gudsnuk, K., Kuo, S., Cotrina, M., Rosoklija, G., & Sosunov, A. et al. (2014). Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits. Neuron, 83(5), 1131-1143. http://dx.doi.org/10.1016/j.neuron.2014.07.040
posted on the HMB website with permission; with special thanks to Umang Khan for sharing their work, as originally submitted in HMB300H1, Fall 2017
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