Dr Iris Oren
University of Edinburgh
Disentangling network dysfunction in Alzheimer's disease pathology: cause, consequence and rescue
The mechanistic link between Alzheimers disease (AD) pathology and impaired cognitive processing remains elusive. Growing evidence, including increased prevalence of seizures and network hyperactivity, strongly suggests a functional disturbance in the cortical network, and in particular, a disorder of inhibitory mechanisms. While cortical inhibition in AD has received relatively little attention, recent evidence suggests that particular sub-components of the inhibitory network are differentially vulnerable. The project will investigate the changes to inhibitory network function in AD pathology in hippocampal CA1, the first hippocampal subregion affected in AD. We will conduct electrophysiological recordings in acute hippocampal slices from APP transgenic mice to identify changes in particular forms of inhibition and their consequences for information processing. We will link the functional changes to anatomical changes and link both function and structure to altered network excitability in vivo. We will proceed to ask what makes particular forms of inhibition susceptible to pathology. Nicotinic receptors composed of ?7 subunits (?7Rs) have been implicated in many aspects of AD and are expressed in CA1 interneurons. Ca2+ imaging and optogenetics will be used to elucidate which interneurons express functional ?7Rs and whether these receptors are associated with pathological inhibitory network changes. To draw a causal inference, interneuron selective ?7R RNA interference experiments will ask whether altering interneuronal ?7R expression can alter pathology in vivo. This research will span functional, structural, causal and interventional approaches at both the single cell and network level, and provide insight into the mechanistic link between pathology and cognitive deficits.