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

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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.