Project No. 2353
Dr Andrew Penn – University of Sussex
Dr Mariana Vargas-Caballero – University of Southampton
A key question in neuroscience is how connections between neurons contribute to information processing and memory storage in the brain.
In the vertebrate central nervous system, the main points of contact and communication between neurons are excitatory synapses. Transmission across excitatory synapses requires both the release of neurotransmitter glutamate from presynaptic neurons and activation of glutamate-activated ion channels in postsynaptic neurons. This project will evaluate the contribution of the NMDA-type glutamate receptors to calcium dynamics and computation at individual excitatory central synapses.
NMDA receptors are fundamental to the regulation of neuronal excitability and signalling between neurons (Hansen et al. 2021), as well as being implicated in neurological disorders (e.g. Elmasri et al., 2020a,b) and to changes in cognition with aging (Warming, et al, 2019; Pegasiou et al 2020). The roles of NMDA receptors are achieved largely thanks to their special attributes, namely their calcium permeability, non-linear current-voltage relationship (due to binding of extracellular magnesium ions), and modulation of receptor function by subunit composition and multiple endogenous ligands.
Current methods to measure synaptic transmission, such as whole-cell patch clamp electrophysiology, are limited in their ability to really evaluate the contribution of NMDA receptor subunits to the operation and efficiency of synaptic transmission due to the measurements being dependent on postsynaptic receptor activation. Recent unpublished work from our lab, using simultaneous multiplex fluorescent imaging of presynaptic glutamate release and postsynaptic calcium, indicates that NMDA receptor subunits contribute differently to excitatory postsynaptic calcium transients. In this project, the student will use existing pharmacological and genetic tools to manipulate NMDA receptor subunit composition in hippocampal neurons/tissue, and then evaluate synaptic function using electrophysiology and multiplex fluorescent imaging. Specific outcomes the student will evaluate include the contribution of NMDA receptor subunits to calcium dynamics at baseline and during backpropagating action potentials (Vargas-Caballero and Robinson, 2003, 2004). This knowledge will inform us about the substrates of information processing and synaptic plasticity in the brain. The project would be suitable for students with both a keen interest in synapse biology and an eagerness to learn a range of lab techniques, including live cell imaging and patch-clamp electrophysiology; these techniques and associated skills and knowledge have applicability in basic and applied research and drug discovery.