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Lab Bootcamp 2019

Wet lab, dry lab, and so much more

In the state-of-the-art laboratory at Ramsay Wright, for the second year in a row, students had the chance to participate in a two-week intensive Lab Bootcamp. In this time, students become familiar with every aspect of #LabLife, from lab techniques to research ethics to transferring lab skills to broader contexts.

This program, initiated by Dr. Dockstader, has the advantage of allowing students to develop their lab skills in a setting that’s not driven by evaluations, encouraging students to go boldly into each activity and make mistakes and, most importantly, learn not just from their instructor but each other as well.

For a glimpse into the Lab Bootcamp experience, take a look below.

Photos by Bernice Datsomor and Zaigham Naqvi

Health in Greece

Professor Maria Papaconstantinou was the co-leader of an International Course Module that took place in Athens, Greece during the February reading week. The focus of the course was the major health concerns in Greece in the context of both the current economic crisis and the ongoing arrival of migrants from war torn countries. Students had the opportunity to learn about the health challenges and the efforts being taken to address them from the perspective of local, national and international organizations. Students met with representatives from organizations including grassroots NGOs, the United Nations International Organization for Migration as well as officials from the Greek Ministry of Health. When they returned, students presented a poster entitled “Understanding the Roles and Perspectives of Various Actors on Health in Athens, Greece” at the Undergraduate Research Forum in March, and produced a YouTube video which can be viewed here:

Gordon Cressy Student Leadership Award Winners

About the Gordon Cressy Student Leadership Award

The Gordon Cressy Student Leadership Awards were established in 1994 by the University of Toronto Alumni Association (UTAA) and the Division of University Advancement in order to recognize students who have made outstanding extra-curricular contributions to their college, faculty or school, or to the university as a whole.

In naming the awards after Gordon Cressy,the former vice-president of development and university relations, the UTAA recognized his commitment to higher education and his leadership in fundraising and community service. The qualities of leadership and dedication demonstrated by Mr. Cressy during his six years with the university are also embodied in the efforts of students chosen to receive this award.

For a complete list of Gordon Cressy Leadership Award winners, please see here.

 

Keep reading to learn more about amazing HMB students and their contributions towards student life

 

Evani Patel

Being a part of the Medical Sciences Student Union (MSSU) has not only been extremely rewarding, but also challenging and demanding given the rigorous course schedules of my program at UofT. Nevertheless, contributing to such a tight-knit student community was one of my most defining moments in undergrad, and learning how to balance various commitments while prioritizing my mental health and academics was an important lesson that I don’t think I would’ve firmly grasped if it weren’t for the inspiring individuals on the MSSU. If I were to give my past-self a piece of advice, it would be to not be too afraid to take risks, trust your gut, and to stay open and vulnerable to changes around you- it’s the only way you will truly mature and become more confident in yourself, and I think my time with the MSSU has definitely proved this to be true time and time again throughout my four years.

 

Amy Freeman

I was Co-President of UofT’s Neuroscience Association for Undergraduate Students. I led a team of student leaders to organize academic and social events for Neuroscience students within the Human Biology program. I was also the Vice President of Professional Development for UofT’s Women in Science and Engineering Chapter. I led the Professional Development team, which provided networking opportunities for female science and engineering students.

 

Ghazal Jessani

Throughout my undergrad career, taking an interdisciplinary approach in my courses and having a wide variety of extracurricular activities was incredibly important to me. I balanced my academics with community involvement through being an executive member of the Women in Science and Engineering team, President of the Ismaili Students’ Association, and founder of YMind (a mental health organization). I am grateful for the opportunities UofT presented and look forward to being an active member in the Harvard community this coming September!

 

Rachel Brunswick

I am honoured to be one of the recipients of the 2019 Gordon Cressy Student Leadership Award. My involvement in student leadership and extra-curricular activities at UofT is responsible for enhancing and enriching my undergraduate experience. I placed importance in finding a community at UofT, not only within my college but within my program of study. For the past three years, I have been an executive member of the Human Biology Students’ Union (HBSU), as Second Year Representative followed by Social Coordinator in both my third and fourth year. My time spent in these roles and being apart of the HBSU executive team allowed the opportunity to create a social and academic community for students within the Human Biology program. The HBSU gave myself, as well as my fellow executives the platform to provide students with resources to achieve their goals, such as attending medical school, as well as providing academic seminars and mentorship programs showcasing careers and research within Human Biology. As my time as an undergraduate student comes to an end, my future plans consist of working towards my goal of attending dental school. I will cherish the memories, experiences, and knowledge that I have gained through my involvement in student leadership at UofT. I look forward to connecting with the alumni network to continue to contribute to the UofT community.

 

Ethan Kim

I majored in Neuroscience and Cell and Systems Biology! While neuroscience was a major passion of mine, I was heavily involved at Innis College through their residence council as well as the College Choir for which I was co-director for two years. I found that having a balance between my studies and extracurricular activities kept me from getting overwhelmed with the workload, and if anything, helped me make friends and foster  a sense of community with the groups I worked with. I couldn’t have done all this without the support from my friends as well as the administration from Innis College!

 

Raumil Patel

I majored in health and disease and biology. I am most proud of my work with the SickKids retinoblastoma team to improve the efficiency and quality of care provided to patients. On campus I enjoyed mentoring first year life science students as part of the HBSU mentorship program.

 

Alexandra Santos

I  am a fourth-year student, double majoring in Neuroscience and Pharmacology. I was the president of the University of Toronto Portuguese Association this year, as well as the Graduating Year Representative on the Neuroscience Association for Undergraduate Students. I was a volunteer and currently an executive on the Brain Waves – U of T Chapter. My neuroscience interests include epilepsy and neurodegenerative diseases. After graduation, I will be working as a full time clinical research assistant at Toronto Western Hospital, studying concussion and various dementias.

 

Danielle Lee

I am a double major in Neuroscience and Nutritional Sciences. I was a Woodsworth College Students’ Association Off-Campus Students’ Director, in which I helped to provide commuters with services in their on-campus experience.

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.

Umang Khan

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.

 

Introduction

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.

Major Findings

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.

Conclusions

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).

Critical Analysis

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.

 

 

Future Directions

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.

References

Bourgeron, T. (2009). A synaptic trek to autism. Current Opinion In Neurobiology, 19(2), 231-234. http://dx.doi.org/10.1016/j.conb.2009.06.003

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

Christensen, D., Baio, J., Braun, K., Bilder, D., Charles, J., & Constantino, J. et al. (2016). Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR. Surveillance Summaries, 65(3), 1-23. http://dx.doi.org/10.15585/mmwr.ss6503a1

Hardan, A., Minshew, N., Mallikarjuhn, M., & Keshavan, M. (2001). Brain Volume in Autism. Journal Of Child Neurology, 16(06), 421. http://dx.doi.org/10.2310/7010.2001.7113

Kaeberlein, M. (2013). mTOR Inhibition: From Aging to Autism and Beyond. Scientifica, 2013, 1-17. http://dx.doi.org/10.1155/2013/849186

Markram, H., Rinaldi, T., & Markram, K. (2007). The intense world syndrome – an alternative hypothesis for autism. Frontiers In Neuroscience, 1(1), 77-96. http://dx.doi.org/10.3389/neuro.01.1.1.006.2007

Markram, K., & Markram, H. (2010). The Intense World Theory – A Unifying Theory of the Neurobiology of Autism. Frontiers In Human Neuroscience, 4. http://dx.doi.org/10.3389/fnhum.2010.00224

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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