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Network maladaptation in response to neuronal injury

Primary Supervisor: Professor Gavin Woodhall, Life & Health Sciences

Secondary supervisor: Dr Stuart Greenhill

PhD project title: Network maladaptation in response to neuronal injury

University of Registration: Aston University

Project outline:

We have recently published evidence of widespread changes in receptor expression following high intensity activity in neuronal networks (Needs et al, 2019). We showed that a wide array of subtypes of glutamate and GABA receptors undergo profound decreases in expression in response to intense neuronal network activity. These changes are limited initially to hippocampus, but as local neuronal network changes manifest, downstream target regions become similarly affected. The electrophysiological profile of neuronal network activity follows the molecular profile, with depression of network oscillatory power. This is followed after months to weeks by the development of network activity that is ultimately unstable and dysfunctional. We hypothesise that downregulation of receptor expression is a fundamental response to neuronal network hyperactivity, leading directly to quiescence in neuronal circuits, which respond via maladaptive homeostatic increase in excitability, and it is this imbalance in synaptic and intrinsic circuit excitability that leads to generation of unstable neuronal network function. 

In people with autoimmune encephalitides, schizophrenia or autism, neuronal network maladaptation compromises normal function but this does not always lead to predictable functional instability, despite ostensibly similar changes in the function of local network elements such as GABAergic interneurons. For example, psychosis often evolves into seizures, and vice versa. We hypothesise that highly cell-type specific and regional deficits in excitatory and inhibitory neurotransmission mediate features of network dysfunction and that similar networks may flip between dysfunctional modes.

We propose to test our hypothesis in an array of animal models of neuronal insult and in human brain tissue taken from paediatric patients at Birmingham Children’s Hospital. We will use electrophysiological, molecular and immunocytochemical approaches alongside our well-established models of neuronal network dysfunction to record in vitro and in vivo, mapping network function to metaplastic changes in receptor expression at synapses onto pyramidal and non-pyramidal neurones in temporal lobe and prefrontal cortex.



BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and Behaviour

Techniques that will be undertaken during the project:

  • Whole-cell patch clamp for miniPSC recordings
  • Western Blotting and immunocytochemistty for receptor identification
  • Organotypic slice culture for human brain experiments

Contact: Professor Gavin Woodhall, Aston University