Through state-of-the-art neurobiological and neural engineering techniques, the Integrative biological psychiatry laboratory is focused on identifying the underlying causes of autism spectrum disorder (ASD), with an emphasis on the contribution of inflammation and the glutamate signalling system within the brain.
The Integrative Biological Psychiatry Laboratory utilises post-mortem neuropathological assessment as well as in vitro models to interrogate pathways of disease that are of interest to us. This includes techniques associated with both gene and protein expression analysis. In addition, at the genetic level we are employing state-of-the-art technology — clustered regularly interspaced short palindromic repeats (CRISPR) — to model if single nucleotide polymorphisms (SNPs) implicated in ASD have functional effects and how these play a role in the underlying aetiology.
Our in vitro models span the use of human foetal brain cultures as well as cell lines and stem cells through a close working relationship with the Stem cells and disease modelling laboratory headed by Assoc Prof Mirella Dottori. Being based at the CfNE allows us the ability to utilise advanced microscopy techniques including Atomic Force microscopy and Helium Ion microscopy for ultrastructure studies while also affording the opportunity of highly novel and innovative neuroscience research through partnerships with electrical engineers and the incorporation of nanotechnology and electrochemical detection.
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Post-mortem brain studies
Through acquisition of brain samples from individuals with ASD and normal controls from the University of Maryland Brain & Tissue Bank (UMBTB) we are conducting a number of quantitative studies to better understand brain pathology in ASD. We have previously demonstrated that a key brain receptor, the metabotropic glutamate receptor (mGluR5), involved in glutamate signalling within the brain is decreased in within the dorsolateral prefrontal cortex (DLPFC). The DLPFC, a frontal brain region known to play important roles in functions that are deficit within individuals with ASD, such as attention and decision making (Chana, Laskaris et al., 2015, Brain, Behaviour and Immunity).
Inflammation, astrocytes and mGluR5
More recently, in collaboration with Dr Karen Gregory and Professor Arthur Christopolous at MIPs, Ms Ting Lee, a PhD student within the IBP laboratory, has demonstrated that mGluR5 may play a role in regulating the activity of astrocytes, a key brain cell that is responsible for providing structural and functional support within the brain. This project involved the activation of astrocytes with an inflammatory molecule, polyinosinic-polycytidylic acid (poly I:C) and the measurement of the number of mGluR5 receptors. We demonstrated that in activated astrocytes there was a decrease in the number of mGluR5 receptors corresponding to a release of pro-inflammatory molecules. This result is interesting as inflammatory changes have been shown to be present within the brains of individuals with ASD and in light of our previous finding of decreased expression of mGluR5 in the DLPC of individuals with ASD. Ongoing work for this project involves using drugs to alter mGluR5 signalling so that we can assess whether they are able to reduce levels of pro-inflammatory molecules in activated astrocytes. This work is complemented by a post-mortem study of astrocytes in the ASD brain that is ongoing, aimed at assessing astrocytes numbers and their activation state compared to control brains.
Inflammation and microglia
Working together with Professor Stan Skafidas and Dr Babak Nasr based at the CfNE, Ms Emma Byers, an honours student within the IBP laboratory, has utilised state of the art helium ion microscopy (HIM) we have generated new and exciting data related to understanding how the brains immune cells, microglia, respond to inflammation. Microglia are increasingly being implicated in the underlying causes of ASD and also in other complex psychiatric disorders such as schizophrenia due to important roles in regulating inflammation within the brain and also because of their more recent roles in being able to prune connections (synapses). Moreover, microglial and synaptic abnormalities have been seen in both of these disorders. Using HIM, this project involved activating microglia with the inflammatory molecules lipopolysaccharide (LPS) and interferon-gamma (IFN-g) and for the first time relating ultrastructure details of these cells morphology to the release of pro-inflammatory cytokines. We have demonstrated that upon activation with both LPS and IFN-g and release of pro-inflammatory molecules, IL-6 and TNf-alpha, we can observe collapse of processes and flattening of the cell surface of BV2 microglia. Conversely, treatment with IL-4 or IL-10 leads to reduced pro-inflammatory molecules and processes that resemble non-treated controls (Figure 1). This work has important implications for understanding microglial functions, with implications across many neurological disorders where microglia are known to be perturbed.
Figure 1: Illustration of collapse of surface processes in LPS and IFN-γ exposed microglia compared to controls. Cells exposed to IL-4 and IL-10 had surface appearance resembling controls.
Making astrocytes and microglia from stem cells
In collaboration with Assoc Prof Mirella Dottori, based at the CfNE, we have started developing protocols for being able to produce astrocytes and microglia from stem cells derived from individuals with ASD. Liliana Laskaris, a PhD student within the IBP laboratory, has successfully been able to demonstrate that stem cells can be used to generate that express microglial markers. This work is ongoing and provides important tools to allow us to grow microglia in the dish from living individuals with ASD in an attempt to recapitulate cells within their brains for more translational outcomes.
Bacterial detection using lab on chip sensor
Through collaboration with Dr Chaturika Abeyrathne and Prof Stan Skafidas based at the CfNE, a novel electrical sensor was developed in order for the rapid detection of bacteria. The research was able to demonstrate the rapid detection of staphylococcus aureus, reducing the time taken from days, through standard microbiological testing to hours. The work has important implications for being able to rapidly detect bacteria in a hospital setting and prescribe appropriate antibiotics to reduce patient burden and decrease development of antibiotic resistance.
In 2016, via the opening of the vault series, run through the Convergence Science Network, this laboratory was able to showcase some of our research activities to the general public. Similar events are planned for the future in order to increase engagement and awareness of research being conducted. The laboratory has also hosted several work experience students through the Melbourne Neuroscience Institute (MNI) and also the Melbourne Neuropsychiatry Centre (MNC). All students who participated had extremely positive feedback about their experience at the CfNE, including:
CfNE was my personal highlight of work experience, and I really enjoyed my time there.
The experience really inspired me to take a closer look at a possible career in neuroscience.
The laboratory also participates annually in the science discovery tours run by the University to allow undergraduate researchers to tour the CfNE and find out what a career in neuroscience entails.
Our goals for 2017
- Expand national collaboration through a project with Dr Jamie Flynn, based at the University of Newcastle, in order to undertake 3D imaging of ASD brain samples using the revolutionary CLARITY technique, whereby brains are made transparent.
- Publication of post-mortem findings for astrocytes in the ASD brain and in vitro studies.
- Increase awareness of our research activities nationally and internationally via conference participation and increased engagement with the public.
- Increase neural engineering based research activities via further engagement with electrical engineers and incorporation of technology into neuroscience applications.
|Dr Gursharan Chana||Senior Research Fellow, Centre for Neural Engineering; Honorary Senior Research Fellow, Department of Psychiatry|
|Prof Stan Skafidas||Director, Centre for Neural Engineering and Clifford Chair of Neural Engineering|
|Prof Christos Pantelis||Scientific Director, Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne|
|Prof Ian Paul Everall||Cato Chair and Head of Department of Psychiatry|
|Assoc Prof Mirella Dottori||Senior Research Fellow and Head, Stem Cells and Disease Modelling laboratory, Centre for Neural Engineering|
|Dr Giovanna D’Abaco||Research Fellow, Centre for Neural Engineering|
|Ms Liliana Laskaris||Department of Psychiatry, Faculty of Medicine, Dentistry and Health Sciences (FMDHS), APA Scholarship
Thesis Title: The Role of Neuroinflammation and Microglial Activation in the Pathogenesis of Schizophrenia
|Ms Ting Ting Lee||Department of Psychiatry, FMDHS, Henry Ackman Travel Awar
Thesis Title: Glial Dysfunction in ASD: Role of mGluR5 and the Glutamatrgic System in Regulating an Astrocytic Response to Neuroinflammation
|Ms Emma Byers||Functional and Structural Investigation of Microglial Activation|
|Prof Anthony Hannan||Head, Synaptic Plasticity Laboratory, Florey Institute of Neuroscience and Mental Health|
|Dr Karen Gregory||Laboratory Head and NHMRC CJ Martin Biomedical Fellow, Monash Institute of Pharmaceutical Sciences|
|Prof Arthur Christopoulos||Theme Leader — Drug Discovery Biology, NHMRC Senior Principal Research Fellow, Monash Institute of Pharmaceutical Sciences|
|Dr Emma Burrows||Researcher Officer, Synaptic Plasticity Laboratory, Florey Institute of Neuroscience and Mental Health|
|Dr Babak Nasr||Research Fellow, Centre for Neural Engineering, The University of Melbourne|
|Dr Chaturika Abernaythe||Research Fellow, Centre for Neural Engineering, The University of Melbourne|
|Dr Thanh Nguyen||Research Fellow, Centre for Neural Engineering, The University of Melbourne|
|Prof Steven Petrou||Associate Director and Head, Division of Epilepsy, Ion Channels and Disease, Florey Institute of Neuroscience and Mental Health|
|Prof Eliezer Masliah||Department of Neuroscience, The University of California, San Diego|
|Dr Vanessa Cropley||NHMRC Post-Doctoral Training Research Fellow, Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne|
|Dr Chad Bousman||Senior Research Fellow, Head, Gene Environment Neuropsychiatry (GENe), Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne|
|Dr Jerome Sarris||Senior Research Fellow, Department of Psychiatry, The University of Melbourne|
|Ms Bernice Lim||University of Melbourne Medical Student Selective|
|Mr Piers Gillett||Department of Genetics, University of Melbourne
Thesis Title: Modulation of the Glutamatergic and Immune Systems in ASD: Role of mGluR5