The aim of my study is to investigate the influence of plasticity within perisomatic-targeting, fast-spiking, parvalbumin-expressing (PV+) interneurons in the hippocampus upon network activity coordinated by these interneurons such as gamma oscillations, as well as upon spatial learning and memory. Gamma oscillations in the hippocampus represent rapid (25-100Hz) synchronized activity of pyramidal cell assemblies driven by fast perisomatic inhibition that regulates pyramidal output. A wide body of evidence implicates the firing of PV+ perisomatic-targeting interneurons such as basket cells and axo-axonic cells as central to the generation of hippocampal gamma oscillations. PV+ cell output, and hippocampal gamma oscillations, have been suggested as important in numerous cognitive processes, including spatial working memory.
It has been proposed that dynamic pyramidal cell assembly formation during gamma oscillations are accompanied by changes in strength at excitatory synapses from pyramidal cells onto PV+ interneurons; furthermore, plasticity has been reported at pyramidal inputs onto interneurons alongside pyramidal assembly formation during spatial learning. We therefore developed an interest in exploring the impact of altering plasticity in PV+ hippocampal interneurons on oscillatory activity and spatial task performance. PV+ interneurons express high levels of calcium-permeable AMPA receptors, capable of mediating NMDA receptor-independent plasticity; as these receptors show minimal expression in pyramidal cells and other interneurons, we aim to selectively target plasticity in PV+ interneurons by pharmacologically and genetically manipulating the activity of these receptors, and therefore elucidate the contribution of said plasticity to circuit dynamics and behavioural phenotypes.
I will accomplish this via a multi-disciplinary approach. I will perform in vitro electrophysiology in the lab of Ed Mann, recording activity at the single-cell and network level. In the lab of David Bannerman, I will perform spatial working memory-based behavioural tasks. With each of these experimental designs, I plan to apply calcium-permeable AMPA receptor-specific drugs to assess the impact of blocking channel receptor activity on electrophysiological profile and behaviour. I subsequently plan to develop and introduce a viral vector that will artificially alter the AMPA receptor profiles of PV+ interneurons in the hippocampus, replacing calcium-permeable with calcium-impermeable AMPA receptors. I will then assess the impact of abolishing calcium permeability, an essential component of plasticity, on electrophysiological profile and behavioural performance.
Reduced expression of the presynaptic co-chaperone cysteine string protein alpha (CSPα) does not exacerbate experimentally-induced ME7 prion disease.
Davies MJ. et al, (2015), Neurosci lett, 589, 138 - 143
After graduating in 2014 from the University of Southampton with a Masters in Biomedical Sciences (First Class), I began reading for a DPhil in Ion Channels and Disease as part of the Wellcome Trust-funded OXION DPhil studentship programme. I completed rotations with Professors David Bannerman and Ed Mann, and have since begun a collaborative project supervised by both these individuals.