Monthly Archives: March 2019

Treating autism spectrum disorders by targeting connections in the brain

By David A. Menassa, @DavidMenassa1, University of Southampton, Neuroscience Theme Lead of The Physiological Society

The United Kingdom has seen a rise in the number of people diagnosed with autism spectrum disorders (ASDs). More recently, some trusts in Northern Ireland have reported a three-fold increase in diagnoses since 2011. Some cases of ASD are linked to a genetic mutation but most of the time, we do not actually know why they occur.

ASD is an umbrella term for disorders characterised by impairments in social interaction and language acquisition, sensory and motor problems and stereotypical behaviours of variable severity according to the Diagnostic and Statistical Manual of Mental Disorders.

Multiple studies report that the physiology and structure of synapses (the gaps between our neurons) are affected in ASDs (1, 2) and that addressing these changes could offer clues for therapy.

The genetic mutations giving rise to different ASDs are predominantly involved in synaptic function. A large-scale analysis of 2000 human brains from individuals with ASDs, schizophrenia and bipolar disorder showed that genes involved in controlling the release of neurotransmitters into the synapse are least active in ASDs (3, 4).

An attempt using the CRISPR/Cas9 gene editing method in a genetic form of ASD known as Fragile-X syndrome (FXS) showed some promise (5). When the researchers turned on a gene that is turned off in this condition, this changed the cells derived from affected individuals from diseased to normal.

Because the number of synapses in ASD post-mortem brains is altered (1), microglia (the brain’s resident immune cells) are thought to be directly involved (as these cells can determine whether synapses stick around) (6-8). Minocycline, which inhibits these microglia, has been used in trials on FXS individuals with promising outcomes including improvements in language, attention and focus as well as an alleviation of core symptoms (9, 10). Furthermore, novel approaches involving inducing microglia to self-destruct (11) or shielding synapses from microglia (12) are being explored. At least in terms of symptom alleviation, addressing synaptic dysfunction and microglia seem to be promising avenues for treatment.

Environmental factors such as changes during pregnancy could contribute to ASD such as the transfer of maternal antibodies against fetal synapses (13) or maternal immune activation (14) or lack of oxygen to the mum or the baby (15). Ways to reduce the risk of injury to the brain with low oxygen in the mum for example have involved delivering antioxidants to the placenta (16). Furthermore, in the early life of the newborn when low oxygen is detected, inhalation of xenon gas combined with cooling also seem to provide promising results that improve neurological outcome (17).

The impact of altered brain development extends beyond the individual influencing their family, carers and the healthcare system. More funding is needed to support this research in order to elucidate the underlying physiology and identify effective treatments.

DAM_Phys_Ref2

This figure illustrates how connections can occur in the ASD brain. Neurons in various colours (black, green and blue) make connections with each other through synapses and some connections are interrupted. Microglia (pink) are near the synapses which we can see in the highlighted squares: in a) a part of the neuron called a dendrite with very few dots on it means there are less synapses than in b) where there are more black dots on the dendrite which means more synapses. These changes represent what we tend to see in post-mortem brain tissue in ASD. Microglia are thought to be involved here by either not clearing away black dots in which case we get more synapses (e.g. typical autism) or by overclearing in which case we have less synapses (e.g. Rett’s syndrome). ASD is otherwise known as a disorder of how connections are established in the brain or a connectivity disorder.

References

  1. Penzes P, Cahill ME, Jones KA, Van Leeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci. 2011;14(3):285-93.
  2. Lima Caldeira G, Peça J, Carvalho AL. New insights on synaptic dysfunction in neuropsychiatric disorders. Curr Opin Neurobiol. 2019;57:62-70.
  3. Zhu Y, Sousa AMM, Gao T, Skarica M, Li M, Santpere G, et al. Spatiotemporal transcriptomic divergence across human and macaque brain development. Science. 2018;362(6420).
  4. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362(6420).
  5. Liu XS, Wu H, Krzisch M, Wu X, Graef J, Muffat J, et al. Rescue of Fragile X Syndrome Neurons by DNA Methylation Editing of the FMR1 Gene. Cell. 2018;172(5):979-92.e6.
  6. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691-705.
  7. Schafer DP, Heller CT, Gunner G, Heller M, Gordon C, Hammond T, et al. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. Elife. 2016;5.
  8. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):1456-8.
  9. Utari A, Chonchaiya W, Rivera SM, Schneider A, Hagerman RJ, Faradz SM, et al. Side effects of minocycline treatment in patients with fragile X syndrome and exploration of outcome measures. Am J Intellect Dev Disabil. 2010;115(5):433-43.
  10. Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell IM, et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 2010;10:91.
  11. Kim HJ, Cho MH, Shim WH, Kim JK, Jeon EY, Kim DH, et al. Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol Psychiatry. 2017;22(11):1576-84.
  12. Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST, Frouin A, et al. CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development. Neuron. 2018;100(1):120-34.e6.
  13. Coutinho E, Menassa DA, Jacobson L, West SJ, Domingos J, Moloney TC, et al. Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero. Acta Neuropathol. 2017;134(4):567-83.
  14. Careaga M, Murai T, Bauman MD. Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol Psychiatry. 2017;81(5):391-401.
  15. Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med. 2007;161(4):326-33.
  16. Phillips TJ, Scott H, Menassa DA, Bignell AL, Sood A, Morton JS, et al. Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development. Sci Rep. 2017;7(1):9079.
  17. Mayor S. Xenon shows promise to prevent brain injury from lack of oxygen in newborns. BMJ. 2010;340:c2005.

Physiology 2019: Something for everyone

By Guy Bewick, University of Aberdeen, UK, Member of local organising committee

Whatever your interest in physiology, be it in research of systems (cardiovascular, respiratory, musculoskeletal, neural, etc.), tissues (epithelia, adipose etc.) or nuclear receptors, or be it in teaching, we have it covered at Physiology 2019, our Annual Conference, in Aberdeen. If the Annual Conference does not quench your thirst for knowledge, why not extend your stay in Scotland’s north-east to attend one of the five Satellite Symposia covering fatigue, obesity, cancer drug cardiotoxicity, and renal and placental physiology.

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The Annual Prize Lecture by Silvia Arber (Basel Biozentrum, Switzerland) will describe her elegant work elucidating the function, assembly and plasticity of motor circuits. The Hodgkin-Huxley-Katz Lecture by Stephen Traynelis (Emory University, Georgia, USA) reveals the characteristics of neuronal glutamate receptors in health and disease. In the Joan Mott Prize Lecture, Claire Hills (University of Lincoln, UK) presents important discoveries in diabetic nephropathy and kidney disease mechanisms. And, finally, the Sharpey-Schafer Lecture by endocrinologist Roger Smith (University of Newcastle, Australia), a leading expert on pathophysiology of human pregnancy, will expound on the idiosyncrasies, interactions and inner workings of the body across species but especially in humans.

A particular teaching highlight will be Dee Silverthorn, whose textbook is a staple of many physiology degree programmes, who will provide insights into best teaching practice from an international perspective.

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Aberdeen’s local representation is by Lora Heisler, recent winner of the Outstanding Scientific Achievement Award from the American Diabetes Association. She will present the Annual Public Lecture describing her work on the neural control of appetite, looking for new targets to tackle the current global epidemic of obesity.

So, please come and join these world-class speakers from across the globe and all stages of their careers who are coming to sample the renowned Scottish hospitality. We look forward to welcoming you to Aberdeen for a memorable summer scientific conference.

Attend our specialist Satellite Symposia, free to Physiology 2019 attendees

Our Satellite Symposia increase the involvement of underrepresented sub-disciplines of physiology at our flagship Annual Conference, Physiology 2019. This year, join us for one of the following five Satellite Symposia. Free to Physiology 2019 attendees, they are all held on Sunday, 7 July 2019. Keep reading for more detail about each meeting, and don’t forget to sign up when registering for Physiology 2019 on our website:
physoc.org/physiology2019/satellite-symposia

Cellular Mechanisms of Anticancer-Induced Cardiotoxicity
Organisers: Susan Currie & Margaret Cunningham from the University of Strathclyde, UK

Cardiovascular disease and cancer are the leading causes of death in the industrialised world. Anti-cancer therapies have dramatically improved over recent years with increased patient survival rates following diagnosis. Kinase inhibitors in particular have had a major impact on cancer patient survival. However, a number of these agents have been reported to cause serious adverse effects on cardiac function, leading to increased numbers of cancer patients with cardiovascular complications that can, in some cases, lead to death. The true extent of the overall risk to cancer patients is unknown, and the underlying mechanism(s) responsible for the cardiotoxic effects remain to be fully identified.

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Strategies to prevent or mitigate cardiotoxicity resulting from cancer treatment are urgently needed to ensure the best cancer care possible. Future management of anticancer-drug-related cardiotoxicity will rely on improved understanding of the cellular effects of these agents in the heart. This, combined with improved biomarker identification along with cardiac imaging for monitoring purposes, will be crucial in an overarching strategy to design effective targeted cardioprotective agents. This symposium will be a forum to bring together basic scientists, cardiologists and oncologists to present recent findings that will work towards this overall goal. Ultimately, collaboration across these disciplines will be essential for promotion of evidence-based research that can relate to clinical practice in the area of anticancer cardiotoxicity.

Fatigue as a Limitation to Performance
Organisers: Derek Ball, University of Aberdeen, UK, and Ron Maughan, University of St Andrews, UK

The complex nature of fatigue is a function of single or multiple mechanisms that result in the failure to produce or maintain the required or expected muscle force/power output. Models to explain the underlying causes of fatigue range from single cell, to organ, to whole body examples and bring together the many different aspects of physiology represented through The Physiological Society.

This symposium will discuss potential limitations to performance imposed by the cardiovascular and respiratory systems, muscle metabolism and the central nervous system and how these factors are modulated by training, environment and nutritional status. In addition, a discussion of the strategies aimed at offsetting fatigue from the perspective of training adaptation and nutritional and pharmacological intervention will be invaluable.

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Physiology of Obesity and Diabetes
Organisers: Lora Heisler, University of Aberdeen, UK, Peter Aldiss, University of Nottingham, UK, Daniel Brayson, King’s College London, UK, and Jo Lewis, University of Cambridge, UK

Obesity is an increasingly common disorder of energy homeostasis and has become a leading cause of type 2 diabetes, cardiovascular disease, human morbidity and mortality worldwide. Exciting new scientific discovery continues to propel the understanding of the molecular, cellular and neural mechanisms underlying the control of metabolic health. Dysregulation of these and other processes underpin the development and progression of obesity, type 2 diabetes and cardiovascular disease.

This symposium will bring together breaking research advances from the basic science and clinical realms with the objective of sharing novel insights relevant to human obesity, type 2 diabetes and cardiovascular disease. Specifically, the meeting seeks to integrate existing knowledge with novel discoveries on appetite, cognitive drivers of feeding behaviour, the gut-brain axis, the neurobiology of ingestive behaviour and energy expenditure, adipogenesis and lipolysis, glucose sensing and glycaemic control, cardiovascular disease and the genetics of obesity and type 2 diabetes. Several new areas will also be addressed, including state-of-art technologies for neuroscience and physiological research, ageing, anorexia and metabolic resilience.

The primary goal of this meeting is to provide cutting-edge research related to the control of body weight and glucose homeostasis. The maintenance of stable body weight involves the biological process energy homeostasis that matches cumulative energy intake to expenditure. The discovery of critical integrative systems that underpin energy homeostasis and glucose metabolism has important implications for the future of obesity and type 2 diabetes treatment. This symposium will highlight the latest advances in the cellular and molecular mechanisms whereby brain circuits modulating physiological appetite and the cognition of food intake are integrated with systems controlling gut function and insulin sensitivity. We will explore the cross-regulation of these circuits by adiposity- and nutrient-related signals.

Renal Physiology: Recent Advances and Emerging Concepts
Organisers: Morag K Mansley and Robert W Hunter from the University of Edinburgh, UK

Renal physiology is flourishing in the UK and beyond. In recent years, physiologists have made fundamental advances: we now know the molecular basis of oedema formation in nephrotic syndrome, how renal sodium and potassium excretion can be controlled independently and how glomerular capillary permeability is regulated. We are also learning much about the influence of the kidney on whole-organism physiology, in particular blood pressure homeostasis including advances in understanding the (renal) mechanism underpinning circadian control of blood pressure.

These recent advances have not only allowed us to better understand renal physiology, but have opened up an array of potential targets for novel therapies in a range of kidney diseases and fluid-electrolyte disorders. The clinical impact of renal physiology research has been demonstrated recently where Vallon and colleagues published a series of papers showing that sodium-glucose co-transporter inhibitors (SGLT2i) can attenuate glomerular hyperfiltration in diabetic rodent models. In 2017-2018, large-scale clinical trials demonstrated that these agents can delay progression of diabetic nephropathy, meaning that – in large part because of basic renal physiology research – we now have the first new effective treatment for this common condition in 15 years. This symposium aims to bring together scientists from across the UK and beyond to discuss the latest advances in renal physiology.

The Placenta and Maternal Metabolic Regulation in Health and Disease
Organisers: Luis Sobrevia, Universidad Católica de Chile, Chile, Raheela Khan, University of Nottingham, UK and Abigail Fowden, University of Cambridge, UK

During pregnancy, many physiological changes occur in the mother, which are designed to support fetal growth and to sustain the baby during lactation. These include changes in the cardiovascular, pulmonary, immune and metabolic systems. A failure to appropriately adapt maternal physiology can lead to pregnancy complications, including abnormal birth weight, pre-eclampsia, and gestational diabetes, which can be traced to poor placental development in early pregnancy. The placenta is the place for bidirectional materno-fetal crosstalk involving transfer of metabolic substrates and epigenetic regulation, about which little is known. Amino acids, lipids, glucose and other substrates such as nucleosides and nucleotides are vital for fetal growth and maturation. However, our understanding of the physiological and pathophysiological aspects of placenta transport mechanisms and the potential consequences for fetal physiology in diseases of pregnancy is still fragile.

The overall goal of this Satellite Symposium is to explore the nature and wider biological significance of placental endocrine function in adapting maternal physiology during pregnancy to support fetal growth in both normal and compromised environments. Discussions will cover insights into regulatory epigenetic mechanisms within the placenta, placental structure and vascular/trophoblast function, contribution of the placenta to disease, placental transfer of nutrients and possible translation to the clinic, and potential consequences of human placenta pathophysiological transfer of nutrients for fetus and newborn health.