MICA: Correction of behavioural, circuit and cellular deficits in rat models of ID/ASD

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Discovery Brain Sciences

Abstract

Intellectual disabilities (IDs) and autism spectrum disorders (ASDs) are co-occurring disorders that are first diagnosed at about 1-2 years of age. They affect approximately 2-3% of the population, between 1-2 million people in the UK alone have an ID/ASD. However, therapeutic approaches for these disorders tend to focus on managing symptoms using special education or medications that target specific symptoms such as anxiety and seizure. There is an urgent need to develop more effective treatments to reverse and/or prevent these brain disorders.
Two areas of research have provided a sea change in how we envision potential treatments for ID/ASD. First, despite the fact that hundreds of genes have been implicated in causing ID/ASD, recent evidence suggests many genetic cause may share changes in brain development and hence treatment developed for one, may be effective for another. Second, while it was previously thought that there treatment would only be effective during early development when symptoms first appear, recent evidence suggests that at least some forms of these disorders may be treatable throughout the lifespan.
Two of the most common genetic forms of ID/ASD are Fragile X Syndrome (FXS) and SYNGAP haploinsufficiency. Both result from genetic alteration of a single gene and hence, are relatively straightforward to study in the laboratory. Previous work from our laboratories indicates that these two disorders may share a common pathology in the hippocampus, the region of the brain responsible for many forms of learning and memory. Using novel rat models of these disorders, we propose to extend these studies to see whether they we also see similar changes in the regions of the brain that control emotion and anxiety, namely the amygdala and prefrontal cortex. We will also test whether any alterations can be prevented from emerging during development and can be rescued in older animals, once ID/ASD related symptoms have emerged. We will test three exciting new drug interventions that are currently being developed for treatment of FXS. Each intervention will be tested for their ability to rescue changes in brain cells, in the connections between brain cells, as well as the behavioural consequences that result from these alterations in brain development.

Technical Summary

Intellectual disabilities (IDs) and autism spectrum disorders (ASDs) are co-occurring neurodevelopmental disorders (NDDs). With a prevalence estimated at 2-3% of the population, between 1-2 million people in the UK alone have an ID/ASD. The urgent unmet need, therefore, is to develop more effective therapeutics to reverse and/or prevent the emergence of the core deficits associated with ID/ASD.

Two areas of research have provided a sea change in how we envision potential treatments for NDDs. First, evidence suggests that genetically disparate NDDs converge on relatively few axes of pathophysiology that are susceptible to common therapeutic intervention. Second, at least some forms of these disorders may be treatable throughout the lifespan. The experiments outlined in this proposal take advantage of two recently developed rat models for FXS and SYNGAP haploinsufficiency, two of the most common genetic forms of ID/ASD. It builds on our recent publications and preliminary data to address these key research areas.

The experiments outlined in this proposal will test our two hypotheses:
1) FXS and SYNGAP haploinsufficiency converge on common pathophysiology in the hippocampus, prefrontal cortex and amygdala.
2) The cellular and behavioural phenotypes associated with loss of FMRP and SYNGAP can be reversed throughout the lifespan in an age, treatment, and circuit-specific manner.

By focusing on two clinically-relevant brain circuits that regulate learning and memory emotion and anxiety/fear we will determine whether deficits associated with these disorders can be prevented and/or reversed as well as whether any beneficial effects are permanent.

Planned Impact

Altered function of the hippocampus and front-amygdala pathway underlie, in part, the emotional/anxiety and altered cognitive function associated with ID/ASD. Despite recent progress in understanding the pathophysiology associated with these disorders, it is not yet clear how universal the underlying synaptic pathophysiologies are between different genetic causes of these disorders. Furthermore, little is know about the development aetiology of these disorders. Finally, currently there are no rational therapeutic interventions available. This project will reveal key mechanisms that link a single gene product to synaptic and functional development of the brain and how it adapts to a changing environment, and will link phenomenological plasticity with cellular mechanisms. It will directly compare, from cell to circuit to behaviour, two of the most common single gene causes of ID/ASD, Fragile X Syndrome (FXS) and SYNGAP haploinsufficiency, to direct test whether they share a common pathophysiology across brain areas. Finally it will examine 3 exiting potential therapies for FXS and determine whether they may also be effective for SYNGAP haploinsufficiency.

The Patrick Wild Centre in Edinburgh and the Centre for Integrative Physiology are ideally placed to exploit basic research findings for societal impact. Both centres aim at translating research into a greater understanding, diagnosis and treatment of mental illnesses. Contacts with the pharmaceutical industry are equally important, as are those with the devolved government of Scotland. On the one hand there is a realistic chance that results from fundamental discovery research may suggest treatment strategies for clinical trials (such as the mGluR5-baesd treatment of Fragile X currently trialed by Novartis, a trial in which the PWC were participants). On the other hand promising research will provide leverage with policymakers in order to ensure that efforts to improve mental health are increased in a manner that is in line with the ever-increasing burden of mental illness on the nation's wealth.

Many members of the public are fascinated by neuroscience and want to know more about how the brain works. The public will benefit from this research through dissemination by our Centres, during open days or events such as Brain Awareness week, and families affected by neurodevelopmental disorders will benefit, in particular from the knowledge that work is being done to better understand and ultimately alleviate these conditions.
 
Description Edinburgh Neuroscience Christmas Lecture - 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was the special invited Edinburgh Neuroscience Christmas Lecture for the public. The lecture was entitled "Understanding Disorders of the Developing Brain in the 21st Century". The event was sold out with around 200 individuals attending.The talk provided an update on the state of research within the field of autism.
Year(s) Of Engagement Activity 2017
URL https://www.edinburghneuroscience.ed.ac.uk/events/christmas-lecture-2017
 
Description Visit from Meeting of the Minds 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Third sector organisations
Results and Impact Meeting of Minds is a parent led support group which gives parents and care givers of children with autism the opportunity to connect with key professionals in a relaxed and friendly environment. They support families in helping their children with additional/complex needs. They also provide the opportunity for parents to meet and support each other. The executive committee of the charity were invited to visit The Patrick Wild Centre in on 13th November 2017. They met with academics working in the field of autism and were given a tour of the research facilities.
Year(s) Of Engagement Activity 2017
URL https://www.facebook.com/Meeting-of-Minds-1609824922672530/