Research Summary
The human brain contains ~86 billion neurons, which communicate through specialized communication ports called synapses. Approximately 80% of cortical synapses use glutamate to relay the signal from one neuron to the other, making it the most abundant neurotransmitter in the vertebrate brain and more than 50% of the brain energy is utilized on glutamatergic signalling. Once glutamate is released into the synapse, AMPA receptors are the first and the fastest proteins to bind it and be activated by it, making them one of the central players in neurotransmission. Changes in the normal behaviour of AMPA receptors can lead to severe neurological disorders, such as epilepsy and complex neurodevelopmental disorders.
At the Biophysics of AMPA-type Glutamate Receptors Group we want to understand the function of these and related proteins involved in synaptic signalling.
We use cellular and molecular approaches in combination with biophysical methods to understand how the structure and function of AMPA receptors enable them to function in the highly dynamic environment of the synapse.
Current projects
1. What is the role of individual subunits in AMPA receptor activation?
AMPA receptors are composed of four subunits whose structure and assembly are well studied, but how this links to function is not yet fully understood. The activation/deactivation cycle of AMPA receptors is extremely fast. Currently, none of the available techniques that measure AMPA receptor activation is fast enough to observe activation of individual subunits. We are developing approaches to slow down AMPA receptor activation in order to overcome this limitation. This will allow us to observe how individual AMPAR receptor subunits contribute to its function. It will also help us understand how certain mutations affect AMPA receptor activity leading to severe neurological disorders.
2. Can we utilize nature's resources to fluorescently label native AMPA receptors in the synapse?
Synapses are very narrow spaces packed with proteins forming a dynamic network of close interactions and undergoing constant protein turnover. Positioning of the synaptic proteins within this dense network is essential for transmission of signals between neurons on a millisecond timescale. This is a changeling environment for microscopy studies as the large external labels commonly used for imaging inevitably disrupt this delicate balance. We are developing a new generation of labels for AMPA receptors inspired by a naturally occurring toxic peptide and designed to minimise interference with proteins within the synaptic space. These novel labels would allow us to study the native function of AMPA receptors in fundamental cognitive processes, such as memory formation and learning, with minimal perturbations to their size and interaction network.
Funding
Our research is funded by:
Startup package from the School of Biological Sciences, University of Edinburgh (2018)
Wellcome - University of Edinburgh Institutional Strategic Support Fund (ISSF3) Award (2019: IS3-R98 and 2022: IS3-R3.04 21/22)
RS Macdonald Seedcorn Fund (2021)
The Academy of Medical Sciences Springboard Award (2022: SBF007\100104)
School of Biological Sciences Seed Fund (2022)
Biomedical AI PhD studentship to Natalia Szlachetka
EASTBIO PhD studentship to Rachael Murray and Alexander Edwards
Daphne Jackson Trust postdoctoral fellowship to Chigdem Mustafa