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

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.

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.

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.