The integrity of rapid signaling between neurons at central excitatory synapses critically depends on the proper function of AMPA-type glutamate receptor ion channels (AMPARs). AMPARs are enriched at postsynaptic sites, where they bind the neurotransmitter glutamate and unconditionally charge the membrane and depolarize the postsynaptic neuron, thereby relaying information from one neuron to the next. Deficiencies in glutamatergic synaptic transmission have been linked to cognitive impairments featuring in many common forms of neuropsychiatric disorder and dementia (Partin, 2015, Curr Opin Pharmacol.). The significance of AMPARs for cognition is clear from the intellectual disability phenotype of patients with mutations in the genes of AMPA receptor subunits (Yuan et al. 2015, Mol Pharmacol.) and from the phenotype of knockout mice (Reisel et al. 2002, Nat Neurosci., Shimshek et al. 2006, J Neurosci).

Over the years, there has been intense and sustained interest in developing drugs to potentiate AMPAR function (Reuillon et al 2016, Curr Top Med Chem.). Much preclinical data supports the treatment of cognitive impairments by pharmacologically targeting AMPARs (Lynch 2006, Curr Opin Pharmacol.). Most efforts to increase the gain of AMPAR-mediated transmission have focused on compounds that potentiate charge transfer through the channel by binding directly to AMPARs at an allosteric site within the glutamate binding domain. These so called Positive Allosteric Modulators' (PAMs) or ampakines stabilize glutamate binding and/or slow AMPA receptor desensitization.

This PhD will use patch-clamp electrophysiology to examine the interaction between ampakines and genetic variants of human AMPA receptors. We are currently funded by the Medical Research Council and have resources and expertise to use a multidisciplinary research approach encompassing computational chemistry, protein production and crystallography, molecular biology, organotypic slice culture, cell culture and patch-clamp electrophysiology. The lab is housed in well-resourced laboratory spaces within Sussex Neuroscience (http://www.sussex.ac.uk/sussexneuroscience/) and the Sussex Drug Discovery Centre (http://www.sussex.ac.uk/sddc/). The PhD studentship is funded by the School of Life Sciences at the University of Sussex.