Category Archives: New research

Star-shaped cells: a clue to differences in schizophrenia pathology?

Dr Vibeke Sørensen Catts is a schizophrenia researcher. Her interests lie in exploring the biological factors that help brain cells grow and die, and how these pathways might be altered in schizophrenia. Here she describes her discovery that certain types of brain cells are inflamed in some people with schizophrenia. This recent finding opens new understanding of what goes wrong in this disorder and how it might be treated.

Dr Vibeke Catts

Dr Vibeke Catts

One of the problems with trying to understand a serious mental illness like schizophrenia is that it doesn’t manifest in the same way in all people. In fact, there is a wide range of symptoms and brain abnormalities across its sufferers, who number 1 out of every 100 people.

My colleagues and I were able to turn this variability to some advantage in our research, by deliberately grouping the people we studied according to the molecular features associated with their illness.

A previous study in the Schizophrenia Research Laboratory had found that one third of people with schizophrenia had high levels of biological markers of inflammation in their brain. The identification of this ‘high inflammatory’ group contributed to an increased understanding among researchers that inflammation contributes to schizophrenia pathophysiology, but the ‘how’ of this process was still not well understood.

Inflammation is a protective bodily response to injury or illness, and in the short term is important for normal processes like muscle growth, but is detrimental over a chronic time course. During inflammatory processes, certain specialised cells are activated, releasing chemicals that regulate symptoms such as swelling and pain. In the brain, this process is known as gliosis, and involves extra growth of the ‘support cells’ of the brain, such as microglia and astrocytes. Earlier studies have shown that microgliosis is present in the brains of people with schizophrenia, but it has not been determined how this links to the increased inflammation in the brain that we had observed in some schizophrenia patients.

To see whether the activation of astrocytes (named for their star-shaped appearance) might be the missing link between a general marker of inflammation such as microgliosis and the other inflammatory markers observed in the brain of this group of schizophrenia patients, we measured a protein called GFAP in the prefrontal cortex of people with schizophrenia. GFAP stands for glial fibrillary acidic protein, and it is a marker for astrogliosis.

Taking a closer look at the brain

We did not find an overall difference in GFAP between people with schizophrenia and healthy controls. This didn’t surprise us, since there is so much variability between schizophrenia patients, and because we had previously observed inflammation in the brain of only a subset, rather than all of the schizophrenia patients. However, when we measured GFAP in that ‘high inflammatory’ subset, this group had increased evidence for astrogliosis than the ‘low inflammatory’ group of schizophrenia patients. Furthermore, the shape of the astrocytes in the ‘high inflammatory’ group was different to the ‘low inflammatory’ group.

Questions, answers, and . . . more questions

Our findings are interesting, but highlight the need for further research. Is the response of astrocytes lower in some people with schizophrenia than in other brain illnesses such as Alzheimer’s disease where inflammation and astrogliosis is abundant? Or perhaps the response starts out normally, but is halted over time due to other factors at play in the illness? For example, antipsychotic medications used to treat schizophrenia symptoms may inhibit the process of gliosis, and so an individual’s exposure to these medications needs to be considered in trying to sort out the contribution of these cellular processes to disease.

Regardless, a continuing discussion of whether gliosis plays a major role in schizophrenia is important. Schizophrenia is considered a disorder of aberrant brain development rather than of brain degeneration. However, our data suggest that it is premature to rule out the idea that some individuals experience a different course of illness such that neurodegeneration associated with inflammation is an integral part of what goes wrong. This would in turn inform tailored treatment development for these people.

Volunteering for stroke research

David Karpin discusses his relationship with NeuRA research from contrasting perspectives as a volunteer and a NeuRA Foundation board member.

Five years ago, as I was sitting watching the morning news, I fell off my chair to the floor. Within the hour I was in hospital, having suffered a severe stroke. Afterwards, I could not walk, speak clearly, or use my left arm or hand. I was totally reliant on other people. My neurologist advised my son I was unlikely to ever walk again.

David practices rehabilitation exercises using the Wii.

David practices rehabilitation exercises using the Wii.

Today, I live independently and can speak clearly, walk unassisted and have partial use of my left arm, hand and fingers. My remarkable transformation is thanks to medical research and in particular to my participation in a stroke rehabilitation study at NeuRA. Using the Nintendo Wii as a rehabilitation tool, this groundbreaking research is translating into results for stroke patients right now, some of whom I introduced to the Wii trial after my own positive experience.

I am now heavily involved in NeuRA activities as a volunteer, donor and NeuRA Foundation board member. The Foundation seeks philanthropic support from different groups and individuals with differing preparedness to give, and I assist with this by sharing my extensive experience in executive administration and management. The overall aim is to enhance the benefits for both the individuals and groups who fund research and also for those who stand to gain meaningful benefit to their lives from research outcomes.

In addition to management experience, good science communication is important in seeking research funding. In addition, it is important to highlight the economic disadvantage of neurological illness to society due to healthcare burden and reduced workforce participation. Many philanthropic partners prefer to support research that translates interventions into clinical practice, and I am glad to say that translational research is an area of strength for NeuRA.

NeuRA has a strong base of ongoing research across a whole array of neurological illnesses. With sufficient funding, we hope it will be possible in future to take on additional areas that have historically been under-resourced but are very important.

I remain involved as a volunteer for a trial being run by a PhD student in the McNulty lab. It is my fervent wish that NeuRA’s research continues to be funded, as it delivers real and very tangible results to the community. Hopefully, you will be inspired to also lend your support. Much more needs to be done to achieve NeuRA’s vision of a society free from diseases and disorders of the brain and nervous system. I hope you and many others will share this vision.

What can our genes tell us about mental illness?

Bipolar disorder affects 350,000 Australians, and has been ranked in the top 20 most disabling disorders globally, making it even more disabling than depression. Dr Jan Fullerton‘s research aims to better understand how genes contribute to bipolar disorder.

Dr Jan Fullerton in the lab

Dr Jan Fullerton in the lab

Bipolar disorder is characterised by oscillating periods of mania and depression. These changes in mood are sometimes accompanied by psychotic episodes and escalating impulsive and risk-taking behaviour, potentially leading to financial and social ruin. While people usually revert to normal mood and behaviour between these episodes, bipolar disorder has a severe impact on its sufferers, increasing suicide risk fifteen-fold.

Bipolar disorder is partly heritable, but we have a limited understanding of the specific genetic causes. By comparing the genetic sequences of many people who have the illness with those of many people who do not, a small number of genetic differences have been identified that individually account for a very small fraction (<1%) of disease risk, but which as a group contribute a larger fraction. However, a large proportion of the genes that contribute to bipolar disorder remain unknown, and it is also not well understood how genetic variation changes the way the brain functions to bring about the illness.

At NeuRA, we are embarking on an exciting new project to identify genes that contribute to the risk of bipolar disorder. Studying a large breadth of the population has been effective in identifying common disease-related variations in genes. However, by studying unique families that have a high density of illness (i.e. more than 4 individuals affected in a family tree), rare gene variants that contribute to disease are more readily identified. We will analyse genetic material from extended families to see whether the disease in those families is due to the collective impact of several rare gene variants.

Pedigree diagram of two families affected by bipolar disorder. Circles represent females and squares represent males.

Pedigree diagram of two families affected by bipolar disorder. Circles represent females and squares represent males.

Using a technology called massively-parallel sequencing we will compare the sequences of the expressed part of the genome (referred to as the ‘exome’: this part of the DNA only constitutes about 1% of the total genome, but is the portion of the genome which directly encodes proteins, which are essential to maintain normal functions of the body). This ‘next-generation’ sequencing technology dramatically increases the extent and accuracy of genetic data over previous methods. We will look for changes in genetic code, even down to a single nucleotide building block (i.e. the A, G, C, or T base), and determine whether there are an abnormal number of copies of a gene in an individual, since sometimes genes (or parts thereof) can be deleted or duplicated. Once these aberrations are identified, we will match them with linkage analysis data to determine whether they are likely to cause the disorder in a specific family. The molecular pathways affected by these genetic factors will be explored, relating novel genes to other genes previously implicated in disease risk.

Our data will be combined with data generated by other members of the international Bipolar Sequencing Consortium and Psychiatric Genomics Consortium to shed light on genes and molecular pathways that are commonly affected in people with bipolar disorder. Once the variants that lead to the loss of gene function in rare, highly penetrant forms of bipolar disorder are identified, the way in which disease risk is inherited will become clearer. This will lead to significant insights into what is actually wrong in the brains of people with this severe illness, and hopefully to new treatment strategies.

Beyond DNA code: epigenetics

Why is it that if you keep an active mental life by playing complicated board games or learning a language, or if you keep physically fit, you are less likely to succumb to dementia?

A/Prof John Kwok is addressing this question by looking at how lifestyle can alter the function of genes related to dementia.

A/Prof John Kwok

A/Prof John Kwok

To do this, he is engaging with the burgeoning field of epigenetics. Genes have to be expressed (i.e. switched on or off) in a tightly regulated manner for our bodies to function correctly. For example, genes get switched on and off when we are born, or when we hit puberty, in response to hormones or tissue growth. While there are parts of our DNA that control how genes are switched on, there are also epigenetic factors, outside our DNA, that can do this. These factors act like a dimmer switch that changes the brightness of a light.

Diet, exercise, and mental activity can ‘dim the brightness’ of genes that might lead to illness, or enhance genes that promote brain health. Not only do these lifestyle factors change gene expression, but their effect might be inherited by the next generation, even if the relevant gene’s DNA sequence itself is not inherited. Understanding the mechanisms of how this happens is a focus of many areas of NeuRA’s work. The study of epigenetics is important in exploring new possibilities for health care.

What about resilience and wellbeing? The flipside of mental illness

Dr Justine Gatt is an NHMRC Research Fellow who has recently joined the NeuRA team. Her research focuses on understanding the flipside of mental illness: why some people are more resilient to stress than others. It is hoped that these characteristics can be promoted in people who may be less resilient.

Dr Justine Gatt

Dr Justine Gatt

In Australia, nearly half of the population experience a mental disorder at some point in their lifetime, with the most common disorders being anxiety or depression. These disorders can occur in anyone, at any age, but adolescents and young adults are particularly vulnerable as their brain is still undergoing the final stages of development. Exposure to trauma or adversity during childhood or adulthood can often trigger symptoms of these disorders. On the other hand, the presence of certain protective factors may make an individual more resilient to the effects of stress and adversity. Notably, the absence of mental illness does not necessarily imply the presence of optimal mental health, and only a small proportion of people who have no mental illness symptoms are actually functioning optimally and are resilient.

Most psychiatric research has focused on understanding mechanisms of risk for different mental disorders and ways to diagnose and treat them. In comparison, there are very few studies that try to understand the mechanisms of resilience. Our research program aims to understand mental health using a new framework. This includes defining the neural underpinnings of resilience using techniques such as magnetic resonance imaging (MRI) and electroencephalography (EEG) measures of brain function. We also examine the genetics of resilience using saliva samples for DNA analysis.

I am currently analysing data from over 1,600 healthy adult twins who participated in the TWIN-E Study of Emotional Wellbeing. Our team has developed a new questionnaire called COMPAS-W to measure wellbeing. It measures qualities, such as composure, positivity, self-worth and mastery over one’s environment, that are self-reported by study subjects. The questionnaire has been validated against objective psychological tests for symptoms of depression and anxiety. Using measures from this broad source base is helpful when linking biological variables like genetics and brain function, and allows us to explore how innate and environmental factors may moderate our wellbeing, with twin heritability estimates at 48%. The good news is that this means that wellbeing is malleable and can be promoted with intervention.

Comparing between twins allows us to determine the relative contribution of genetics and environment to changes in the volume of grey matter in different parts of the brain. Changes are highlighted in colour. (Gatt et al 2012, Twin Research and Human Genetics)

Comparing identical and non-identical twins allows us to determine the relative contribution of genetics and environment to differences in the volume of grey matter in different parts of the brain. Differences are highlighted in colour. (Gatt et al 2012, Twin Research and Human Genetics)

Another aspect of our research tests how interventions work to promote resilience. We are working with industry partners to test different e-health tools. One of these tools, called MyBrainSolutions, provides targeted, personalised emotional and cognitive solutions over the Internet. To measure resilience, we are testing games that promote positivity (e.g., gratitude training and positive affirmations) and stress management (e.g., the negative thought challenger and MyCalmBeat), as well as executive control games that aim to boost working memory, attention, and goal setting.

Understanding the biology of resilience is the first step towards personalised health solutions. It provides the foundation of features that could be nurtured in low-resilient individuals in order to prevent psychiatric illness. This ‘resilience bio-signature’ could be used as a diagnostic tool for predicting risk for developing mental illness following trauma. At-risk children or adults could then be provided with simple tools to train them to better adapt to life stressors and make them more resilient for the future.

Justine was recently awarded a competitive National Health and Medical Research Council (NHMRC) Career Development Fellowship to conduct this research program. As evidence of innovation and research excellence, Justine was lucky enough to receive the Commonwealth Health Minister’s Award for Excellence in Health and Medical Research in June 2014. The TWIN-E study was a collaborative study with Prof Leanne Williams (Stanford University, previously University of Sydney) as Chief Investigator and co-investigators Prof Peter Schofield (NeuRA), A/Prof Anthony Harris (University of Sydney), Prof Richard Clark (Flinders University), and Dr Justine Gatt (previously as ARC APDI postdoctoral research fellow, University of Sydney) and supported by an Australian Research Council Linkage (LP 0883621) grant with Brain Resource as industry partner.



Contracture: understanding mechanisms and testing treatments

As part of a new National Health and Medical Research Council Program Grant on motor impairment, Prof Rob Herbert aims to advance the transfer of new understanding of physiology and pathophysiology in motor impairment toward the clinical outcome of improved motor function.

Prof Rob Herbert

Prof Rob Herbert

Motor impairment is a common consequence of a number of illnesses and injuries. One type of motor impairment that is an important cause of physical disability is muscle contracture. A contracture is a stiffening of the muscles that limits normal joint movement, and severe contractures cause deformities that are the most visible manifestation of brain damage. Contractures arise when brain lesions, including those that arise from stroke or traumatic brain injury, cause paralysis or spasticity. Paralysis and spasticity change the mechanical environment of muscles – that is, they cause muscles to experience different patterns of activity, different changes in length and different forces than would normally be experienced. The muscles adapt in response to their altered mechanical environment by becoming stiffer, causing joints to become less mobile.

Contracture is a common problem. In a recent study, my colleagues and I monitored 200 consecutive people admitted to a Sydney hospital with the diagnosis of stroke. Six months after admission, half of all those people had developed at least one contracture. Contractures are also common in people with many other sorts of brain lesions. For example, contractures are prevalent in people who have had a traumatic brain injury, or who have multiple sclerosis or cerebral palsy.

Contractures prevent joint movement, so they cause physical disability. For example, many people who have had a stroke or traumatic brain injury develop contractures of the calf muscles. Calf muscle contractures impede ankle motion, making it difficult to stand up from a chair or walk normally. In the same way, contractures of shoulder muscles can impair the ability to reach and contractures of wrist and finger muscles can impair grasp. Severe muscle contractures can cause the limb to adopt a fixed position. For many people, contractures become a much greater impediment to normal movement than the paralysis or spasticity that initially caused the contracture to develop.

There has been surprisingly little research into the mechanisms of contracture. As a result, the mechanisms are poorly understood. Studies on animals have shown that it is possible to make muscles become short or stiff with a number of experimental procedures. For example, leg muscles can be made short by immobilising the leg in a plaster cast, and diaphragm muscles can be made short by inducing emphysema (a lung disease). These studies show that the stiffening of muscles can occur either because of changes in the muscle tissue (the muscle “fibres” or “fascicles”), or because of changes in the tendons that join muscle fascicles to bones. But studies on animal muscles can’t tell us about the mechanisms of contractures seen in human populations. Surprisingly, it is still not clear whether contractures in people who have had a stroke or traumatic brain injury are due to changes in the muscle fascicles or tendons.

There is just as much uncertainty about how to prevent and treat contracture. For the last half-century, physiotherapists and nurses have applied stretches to muscles, or passively moved limbs, or applied splints or casts to stretch the limb, with the aim of preventing or treating contractures. But recent research suggests these interventions have little effect. For example, in one study, 63 volunteers who had experienced a stroke were randomly allocated to receive either a wrist splint or no splint. Two months later there was no discernable difference in the stiffness of the wrist of people who had or had not been splinted. There have now been over 35 studies like these, and they quite consistently show little or no effect of stretch or movement-based interventions. For now at least, there are no treatments that have been clearly shown to prevent or reverse contracture.

Eventually, scientific research will provide answers, both about the mechanisms of contracture, and about how to prevent and treat contracture. The first steps have been made in identifying the abnormalities of gene expression that are ultimately expressed as contracture. New ideas for treatments are being generated by basic research, for subsequent testing in clinical trials. Our motor impairment program will study human volunteers and patients to learn more about normal motor function and the mechanisms of motor impairment, and to test the clinical efficacy and mechanisms of novel treatment interventions. The development of new techniques for imaging and measuring the internal architecture of muscles using MRI provides one promising advance. One study will look at how muscle tendons and fascicles are recruited during movement, which will inform subsequent clinical studies in people in whom contracture is common, such as people with stroke, spinal cord injury and multiple sclerosis.

Hopefully, the next decade will see major advances in both our understanding of the mechanisms of contracture and how to treat them.

An example of one of the unique muscle images generated by Prof Herbert's team. In the centre is a human leg muscle. The blue lines show the course of muscle cells in six locations in the muscle. The insets provide information about how the cells terminate on the tendinous sheets that cover the upper and lower surfaces of the muscle.

An example of one of the unique muscle images generated by Prof Herbert’s team. In the centre is a human leg muscle. The blue lines show the course of muscle cells in six locations in the muscle. The insets provide information about how the cells terminate on the tendinous sheets that cover the upper and lower surfaces of the muscle.

An international approach to tackling Parkinson’s disease

Dr Nic Dzamko and Prof Glenda Halliday have put together an international team dedicated to researching the causes of Parkinson’s disease. They will be the first in the world to use valuable early clinical samples to identify the genetic and molecular underpinnings of this brain illness.

Parkinson’s disease is a debilitating neurodegenerative disorder with no current cure. 1 in every 30 Australians is diagnosed with Parkinson’s disease, and these numbers are predicted to rise. Over the last 10-15 years, it has emerged that genes play an important role in the risk of developing Parkinson’s disease. Approximately 16 genes have now been identified that increase the risk of developing Parkinson’s disease. Understanding what these genes do in the healthy brain, and how their functionality might go wrong, has become a major focus in the search for clues about the cause of this disease.


Dr Nic Dzamko in the laboratory

One of these genes, called LRRK2, has received considerable attention. The LRRK2 gene encodes a protein that belongs to a class of enzymes called kinases, which is interesting to researchers because many anti-cancer drugs developed by the pharmaceutical industry also act by blocking kinases. In the past few years, more than 20 drugs that can block the kinase LRRK2 have been patented. While it is hoped that these drugs may be beneficial for the treatment of Parkinson’s disease, more work needs to be done to understand exactly what LRRK2 does, and therefore whether drugs that block its action will be safe and therapeutically useful. To better understand the function of LRRK2, our team at NeuRA has initiated two new projects in collaboration with scientists from around the world.

The first project involves us leading a group of scientists from London, Tokyo, California and the Netherlands. Using 400 samples that have been sent to us from these locations, and that cover a range of brain regions at different disease stages, we will determine if, when and where the expression of the LRRK2 enzyme goes wrong in the Parkinson’s brain.

The second project aims to investigate the idea that inflammation is linked with Parkinson’s disease, in collaboration with researchers in the US and Europe. This project is particularly exciting, as it may identify much-needed markers of early disease. By working with the worldwide LRRK2 Cohort Consortium, established by the Michael J Fox Foundation for Parkinson’s Research, we have access to more and better samples to ultimately obtain more meaningful data. We will measure a range of biological markers associated with inflammation in serum and cerebrospinal fluid. By comparing the extent and type of inflammation in people who do and do not have certain genetic mutations, and between people with Parkinson’s disease and healthy controls, we will identify whether inflammation is an early sign of Parkinson’s disease. This world-first access to blood samples from people with a large genetic risk of getting Parkinson’s, but who do not yet have the disease symptoms, is a chance to try and identify potential treatments for the early stages of this illness.

These projects have taken about a year and over 300 emails to come together. Although meetings are often scheduled in the very early hours of the morning to accommodate time zones, working together as an international team to leverage skills and resources is an important step toward solving the problem of Parkinson’s disease. Of course, our work would not be possible without the funding we have received for these projects from the Michael J Fox Foundation and the Shake it Up Australia Foundation.

The life of an early career researcher

An early career researcher is an interesting creature – focussed, driven and often self-critical. Outgoing Chair of the Early Career Committee (ECC) at NeuRA, Kirsten Coupland, explains what it is like being a young scientist and the role the committee plays in supporting careers.

Early career researchers are those working in science who have completed their PhD less than six years previously or who are under the age of 40; whether studying or employed, involved in academia, or industry. There are around 120 early career researchers currently at NeuRA but this number fluctuates as people take exciting steps in their careers. These researchers are just discovering what a career in research entails. They are finding that a scientific career is not as structured as one in the corporate world; skills are learnt on the job and successful outcomes to experiments often initially elude them. Young researchers learn at the deep end. The work of the ECC, of which I am the outgoing Chair, is important for young researchers at NeuRA. We provide events and seminars that develop the skills and professional attributes young researchers need to cultivate a successful career in science.

What it takes to be a scientist

The world of research is extremely competitive and many of the things that set one scientist apart from the crowd are less tangible than research results. Being a good scientist requires the ability to communicate, have a strong network, a comprehensive knowledge base and confidence.


Kirsten Coupland in the laboratory

What we do 

NeuRA’s ECC aims to give young researchers the ability to cultivate these assets and enjoy themselves at the same time. Events the ECC orchestrates encourage young researchers to interact with new people from different research groups. In doing so, they not only become confident at communicating their research to scientists from other fields, but they also start developing a network they will use throughout their career. Initiatives include regular seminars featuring speakers from around the country who discuss topics such as ethics, social media, and where to source funding.

Panel discussions of post-docs or non-academic science careers have helped get early career researchers thinking about what they will do with their scientific knowledge. Informal coffee meet-ups allow students to discuss their research with a mixed audience and interact with people they may not know at NeuRA. Early career researchers are the future generation of scientific research. It is important they have the skills and attributes necessary to carry out creative and exciting science that will revolutionise the way we understand the human body.    

Cannabidiol – a glimmer of hope for Alzheimer’s disease?

Alzheimer’s disease is the most common form of dementia, which affects around 330,000 Australians. In 2009 – 2010, the healthcare cost of dementia was over 4.9 billion dollars in Australia. Both of these figures are on the rise, given that our life expectancy is increasing.

People living with Alzheimer’s disease experience a range of symptoms that include social withdrawal and problems with remembering places, objects and people, and these symptoms become progressively worse with time. In the brain, aside from the increasingly well-recognised amyloid plaques and tangles, imaging and post-mortem analyses have also found extensive neuronal degeneration, inflammation, toxicity and oxidative stress, and these processes are likely to contribute to the development of Alzheimer’s disease.

Current treatments are unable to stop the disease progression, and the quest to find a viable treatment for Alzheimer’s disease continues. Many treatments have been designed to target single brain systems that are affected in Alzheimer’s disease. However, this approach is not sufficient for two reasons: 1) more than just one system is affected in the disease, and 2) it may be too late to administer these treatments once the disease has been diagnosed. Research now suggests it may be more beneficial for patients if treatments targeted a range of systems that are altered in Alzheimer’s disease and could be administered early, perhaps even before disease symptoms are prominent, as a method of prevention.

So where does one find a treatment that can exert neuroprotective, anti-oxidant and anti-inflammatory effects all at once? Well, the answer might lie in a compound known as cannabidiol. Cannabidiol has been shown to have all the above properties, which could be relevant for Alzheimer’s disease. However, there have been only a few studies that have followed up on this link, perhaps because many people might be eager to dismiss cannabidiol as a treatment due to concerns that it may exhibit the psychoactive properties of other compounds obtained from the cannabis plant. But in fact, cannabidiol is behaviourally inactive in humans when taken over long periods of time, including in people with schizophrenia and Huntington’s disease. Cannabidiol also prevents the memory-impairing effects of THC, the main psychoactive compound of cannabis. And, in promising news for Alzheimer’s research, cannabidiol has also been shown to reduce amyloid production and increase neurogenesis in brain cells. With this in mind, it is only logical that cannabidiol should be tested for its potential to benefit those with Alzheimer’s disease, as it might counter some of the main biological changes that are occurring.

David Cheng has just completed his PhD at NeuRA under the supervision of Dr Tim Karl.

David Cheng has just completed his PhD at NeuRA under the supervision of Dr Tim Karl.

My study, published in the journal Psychopharmacology, was the first to investigate the effect of cannabidiol treatment in a transgenic mouse model of Alzheimer’s disease. This mouse model carries two genetic mutations that are associated with familial Alzheimer’s disease, and the mice show behaviours that are relevant to Alzheimer’s symptoms, such as social recognition and spatial memory deficits. Since normal mice have a tendency to explore either new things or other mice, we compared how well transgenic mice fared in a test called the social preference test, which measures the amount of time that the test mouse spends exploring either a familiar or a new (never before seen) mouse. I discovered that the Alzheimer’s model mice spent the same amount of time exploring both the new and familiar mice, showing that they were unable to tell the difference between the two. Excitingly, daily cannabidiol treatment given over 3 weeks restored the social recognition memory of the transgenic mice.

In a separate study, soon to be published in the Journal of Alzheimer’s disease, cannabidiol was given to the transgenic mice every day, beginning at a very early age, to test whether it can be administered early as a prevention against the social recognition memory deficits. Promisingly, the development of recognition deficits in the disease model mice was prevented by the cannabidiol treatment. Using various biochemical techniques, I also found evidence to suggest that this effect might be mediated by the anti-inflammatory properties of cannabidiol.

These findings are extremely interesting as they show cannabidiol might have behavioural and biological effects that could benefit people with Alzheimer’s disease. Of course, we know that mice are not exactly like humans, but mouse models give researchers a great amount of insight into the effects of Alzheimer’s disease genetic mutations on both behaviour and biology. For example, links can be drawn between the social recognition deficits displayed by the Alzheimer’s disease model mice and the inability to recognise familiar faces in people with Alzheimer’s disease. Imagine what it would mean for people with Alzheimer’s disease and their friends and relatives if they could still recognise their loved ones! With more research, it will be possible to gain a better understanding of the exact mechanisms behind the beneficial effect that cannabidiol has already shown in this mouse model, paving the way for possible clinical trials in the future.

Building blocks for a fresh understanding of schizophrenia

Dr Dipesh Joshi received this year’s Leslie Kiloh paper award for his work into the understanding of schizophrenia. Since then, he has published new work linking problematic neurons to a genetic abnormality associated with schizophrenia.

He explains how his work has created a greater understanding of this disease.

Genes are a precious gift that every generation passes on to the following one since the existence of mankind. Abnormal functioning of some of these genes may lead to abnormal functioning of the brain cells leading to development of brain disorders. NRG1 and ErbB4 are two such genes that have been identified as ‘schizophrenia risk genes’.

Altered functioning or signaling of these genes contributes to the development of schizophrenia. Research shows that there are physical differences in the brains of people with schizophrenia compared with those of healthy people. To identify how genetic abnormalities lead to such physical differences remains a significant challenge. If this was known, we would be closer to understanding exactly what happens in the brain to cause the symptoms of schizophrenia, such as social withdrawal, difficulty with memory and planning, and even hallucinations, all of which can be very distressing to an individual with the illness.

What drug treatments are available now?

These days, the available antipsychotic treatments are relevant only for positive symptoms such as hearing voices, suspiciousness, feeling as though you are under constant surveillance, delusions, or making up words without a meaning, but not for negative symptoms which might include social withdrawal, cognitive deficits, difficulty in expressing emotion and an inability to feel pleasure. This highlights the urgency of having new antipsychotic drugs that have beneficial effects in treating negative symptoms and cognitive deficits in people with schizophrenia.

What are the risk genes doing in schizophrenia?

Dr Dipesh Joshi is a postdoctoral research officer at NeuRA

Dr Dipesh Joshi is a postdoctoral research officer at NeuRA

Our recent research work has been able to link schizophrenia risk genes (NRG1 and ErbB4) with a type of brain cell which maintains the inhibitory-excitatory balance in a normal brain. In schizophrenia, this particular brain cell-type, called inhibitory interneuron has been found to be reduced compared to healthy individuals. Research conducted in our laboratory is completely unique as it shows how an increase in the risk gene (ErbB4) is linked with a reduction in inhibitory brain cells. Increased levels of ErbB4 gene contributes to the inhibitory-excitatory imbalance resulting in development of schizophrenia.

These findings are crucial for brain researchers to understand how schizophrenia ‘risk genes’ adversely affect brain cells resulting in brain abnormalities found in people with schizophrenia. Our findings are a step forward in identifying new therapeutic targets for a new generation of antipsychotics that will have beneficial effects that extend beyond positive symptoms in people with schizophrenia and for us that is a very exciting prospect.


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