Professor Andrew Randall, Medical School, College of Medicine and Health, University of Exeter
Dr Jonathan Witton, College of Medicine and Health, University of Exeter
Prof Jack Mellor, School of Physiology, Pharmacology and Neuroscience, University of Bristol
The main symptoms of Alzheimer’s disease (AD) are learning and memory loss. Remodelling of neural circuits through the formation and elimination of synapses is key to these cognitive processes. Recent evidence has revealed the importance of remodelling inhibitory synapses in cognition, but little is known about how this is affected in AD. We will study this using cutting-edge in vivo two-photon brain imaging.
Aim: Characterise progressive Alzheimer’s disease (AD) pathology-mediated changes in synaptic remodelling in distinct subtypes of inhibitory interneurons in vivo.
Background: Learning and memory are fundamental cognitive processes that are disrupted in AD. Key to these processes is the remodelling of neural circuits through the formation and elimination of synapses. AD causes synapse loss, and synaptic remodelling in excitatory principal neurons is known to be disrupted by amyloid beta (Aβ) pathology, a hallmark of the AD brain. However, almost nothing is known about the effects of Aβ pathology on synaptic remodelling in inhibitory interneurons.
Temporally coordinated activity between excitatory neurons and inhibitory interneurons supports cognitive processes such as learning and memory. Evidence from human and mouse studies, including those of our group (Witton et al. J. Physiol. 2014), suggests these coordinated interactions break down early in AD. Abnormal functional changes have been identified in several interneuron subtypes in Aβ overexpression models, but of these, fast spiking parvalbumin (PV)-expressing interneurons seem to be particularly vulnerable, exhibiting decreased excitability and reduced strength of synaptic transmission. Since synaptic remodelling is an activity dependent process, such functional changes would also be expected to alter the anatomical connectivity of these interneurons, leading to aberrant rewiring of inhibitory brain circuits.
Hypothesis: Abnormal synaptic remodelling in inhibitory interneurons is a key pathophysiological event in AD, and fast spiking parvalbumin (PV)-positive interneurons are particularly vulnerable to this disruption compared to other interneuron subtypes.
Experimental design: The student will use in vivo two-photon microscopy to study the relationship between Aβ pathology and the anatomical remodelling (plasticity) of dendritic spines, axonal boutons and their respective parent neurites in PV-expressing (typically fast spiking) and SOM-expressing (non-fast spiking) interneurons in a mouse model of AD.
PV-Cre or SOM-Cre driver mice (available in Bristol) will be crossed with hAPP-J20 mice (available in Exeter) to express Cre recombinase selectively in PV or SOM interneurons in mice that age-dependently develop Aβ pathology. A fluorescent marker of neuronal structure (EGFP) will be expressed in each interneuron subtype using viral transduction under the Cre-Lox system.
Fluorescent dendrites and axons will be imaged in vivo through a chronically implanted glass cranial window. Structural changes (e.g. gains and losses) in dendritic spines, axonal boutons, and their parent neurites will be tracked by imaging the same neurites at regular intervals across a 3 month period corresponding to the prodromal phase of disease in hAPP-J20 mice (3-6 months of age). The development of Aβ pathology will be simultaneously detected by labelling with the fluorescent probe methoxy-X04. Longitudinal image series will be analysed using custom computational analysis routines written in ImageJ and Matlab software.
Outcome: This project will define the relationship between the progressive development of Aβ pathology, a hallmark of AD, and changes in the remodelling of synaptic connectivity in inhibitory brain circuits. We hope to add to emerging evidence showing that disruption of inhibitory interneurons is key in AD, and that targeting inhibition could therefore be a viable strategy for AD treatment.
To apply for this project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl
by 5pm Friday 25 November 2019.