The neuropathophysiology associated with Syngap mutations: further evidence for an mGluR5 signaling axis in ID/ASD

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Integrative Physiology

Abstract

The human brain contains upwards of 100 billion neurones (nerve cells) which form a network that acts as an 'information superhighway' that continuously sends and receives signals, processing these to control every aspect of our behaviour - from simple, but fundamental, tasks such as breathing and walking to the complex such as perceiving emotion, interpreting our senses and storing and recalling memories. Neurons 'communicate' with each other at specialized sites known as synapses - a site where one neuron releases a chemical (known as a neurotransmitter) that binds to specific proteins (receptors) on the second neuron. It is estimated that there are around 100 trillion synapses in the human brain. In humans suffering from intellectual disability (ID; defined by an IQ <70) it is thought than the process of synaptic transmission is disrupted such that the "superhighway" does not operate as effectively as it should.

Scientists have been able to identify some of the proteins whose function is disrupted or which are missing is certain forms of ID. Our proposal focuses on studying one of these proteins, called SynGAP, which when it fails to function normally results in ID in humans. Using genetic techniques, a mouse has been created which has altered SynGAP function and which is considered to be a very good animal model for ID in humans. Our proposal hypothesises that some of the defects in synaptic transmission that are seen in humans with altered SynGAP function might be the result of changes in a common signalling pathway that is also seen in another form of ID called fragile X syndrome (FXS). The good news is that clinical trials are presently underway which are attempting to correct some of the changes in synaptic transmission seen in FXS. We want to see if, in our animal model, the defects seen with SynGAP can be corrected by drugs which are currently being trialed for the treatment of FXS. If our hypothesis is correct this will demonstrate that two (and perhaps more) forms of ID are actually linked, providing hope that treatments that work in one form of ID might also be useful in another.

Technical Summary

SYNGAP is a key signalling enzyme that is highly abundant in the postsynaptic density where it regulates glutamate receptor signalling. De novo truncation mutations of a single copy of SYNGAP lead to autosomal dominant non-syndromic intellectual disability (NSID). A recent study of 155 cases of NSID showed that 6 (4%) had mutations in SYNGAP. If this prevalence is extrapolated to the entire population, mutations in SYNGAP may be amongst the most common causes of ID (for comparison fragile X syndrome (FXS) accounts for <1% of ID). Our proposal stems from the fact that there is a significant convergence in the pathophysiological consequences of genetic deletion of Fmr1 and a single copy of Syngap in mice - both show exaggerated and protein synthesis-independent mGluR5-induced LTD, both transgenic lines have increased locomotor activity and show impaired spatial and associative learning. Developmentally, SynGAP and FMRP show a similar time-course of expression and both mutants show reduced cellular segregation without altering the whisker pattern of thalamocortical axons in somatosensory cortex. Furthermore, both show alterations in dendritic spines. Taken together, these findings have led us to hypothesize that SynGAP, like fragile X mental retardation protein (FMRP), is part of the mGluR5 axis of ID and phenotypes associated with the loss of SynGAP will be rescued by reducing mGluR5 signalling - as they are in mouse models of FXS. To address this hypothesis we will utilise the experimental strength of two brain regions, the hippocampus and the primary somatosensory cortex. Both brain regions have been extensively studied in Fmr1-/y mice. The former has provided the prototypical phenotypes associated with the loss of FMRP. The latter has provided essential insight into the developmental role of FMRP and provides an excellent system to elucidate the pathophysiology of genetic mutations form synapse to circuit.

Planned Impact

The primary somatosensory and hippocampus have long been key areas in the brain for studies of synaptic plasticity, which in turn sheds light on learning processes more generally. Despite much progress, it is not yet clear how universal the underlying synaptic pathophysiologies are between different genetic causes of these disorders. 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 is becoming increasingly evident that many neurodevelopmental disorders such as intellectual disability and autism spectrum disorder involve defects and malfunctions at the cellular and synaptic level. A better understanding of the role of individual genes in synaptic plasticity will contribute to the search for treatments of these disorders and eventually benefit public health at large.

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 trialled by Novartis, a trial in which the PWC participates). 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.

Publications

10 25 50
 
Description MRC Project Grant
Amount £1,352,057 (GBP)
Funding ID MR/P006213/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2016 
End 08/2020
 
Description Research Centre Grant
Amount रू 670,000,000 (INR)
Organisation Ministry of Science and Technology India 
Department Department of Biotechnology, India
Sector Public
Country India
Start 06/2014 
End 05/2019
 
Description Simons Initiative for the Developing Brain
Amount £20,000,000 (GBP)
Organisation Simons Foundation 
Department Simons Foundation Autism Research Initiative
Sector Charity/Non Profit
Country United States
Start 04/2017 
End 03/2022
 
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 Talk at Scottish Fragile X Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk to inform of current research surrounding Fragile X Syndrome and other forms of ASD and discussion afterwards.

Continued engagement with a primary stakeholder (families) in the Patrick Wild Centre.
Year(s) Of Engagement Activity 2014
 
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/