*BBSRC EASTBIO Programme* Is there a role for GABA-A receptor alpha-5 subunits in cognitive deficits caused by consumption of a high fat diet?

Project Synopsis: This project will use dietary manipulations in mice and look at behavioural effects on memory alongside electrophysiological changes in synaptic plasticity and changes in receptor expression in the brain. It will investigate the question of whether GABA-A receptor alpha-5 subunits, a target for cognitive enhancing drugs, are upregulated by a high fat diet and whether this is linked to inflammatory cytokine activation. It aims to define a mechanistic link between fat consumption and memory loss.

Background: Cognitive deficits in mice appear within days of initiating high fat feeding. This models cognitive decline seen in Type II diabetics and in fact in healthy young subjects with a high BMI (1). We  have  previously  demonstrated  that  a  high-fat  diet  (HFD),  in mice,  rapidly  and dramatically impacts  on  complex  associative  episodic-like  memory,  which  incorporates information  about  specific  events,  including  spatial  locations  and  the  contextual features  of the  environment  in  which  the  event  took  place (2). Episodic memory  is one of the  memories initially  compromised  in  Alzheimer’s  disease  and  is  located  in  the  hippocampus. These cognitive deficits could be caused by the activation of inflammatory cytokines such as the interleukins, which are thought to modulate GABA-A receptor function (3). GABA-A receptors containing the alpha-5 subunit are found in a high density in the hippocampus and are involved in learning and memory. Downregulating these receptors can be a method of cognitive enhancement which has been shown in healthy human volunteers and is currently in clinical trials for Down’s syndrome. Could these receptors could be a link between high fat feeding and cognitive decline, potentially due to their activation by inflammatory cytokines?

Experimental plan:

1. Show that high fat feeding in mice causes specific and rapid deficits in memory (technique: dietary manipulation and behavioural testing in vivo- Dundee)

2.  Investigate whether administration of drugs affecting GABA-A alpha-5 can reverse the cognitive                                                 deficits seen with high fat feeding (in vivo neuropharmacology and behaviour- Dundee)

3.  Study the expression of alpha-5 and interleukins and their correlation with cognition (in situ     hybridization- Aberdeen)

4. Examine hippocampal synaptic plasticity and the role of alpha-5 in the brains of mice who have been high fat fed (in vitro and in vivo electrophysiology- Dundee)

Supervisors: Dr Langston and Prof Williams have recently shown in a joint PhD studentship (EastBio, current) the rapid effects of high fat diet on a suite of sensitive translational behavioural tests for mice. Dr Langston and Prof Lambert currently collaborate on multiple funded projects examining the role of the GABA-A receptor alpha-5 subunit in cognitive decline associated with neurodegenerative disorders. This team of supervisors and their laboratories will provide a range of techniques and experienced mentors to take forward this exciting research area. The behavioural and electrophysiological (in vivo) work will be carried out in Dundee (75%) with molecular pharmacology work in Aberdeen (25%).

References:

(1) Cheke LG, Simons JS, Clayton NS (2016) Higher body mass index is associated with episodic memory deficits in young adults. QJEP 69(11):2305-16

(2) McLean FH, Langston RF, Campbell FM, Lorenzo-Arribas A, Williams LM (2014)   Episodic-memory is  rapidly  compromised  by  a  high-fat  diet  in  C57Bl/6  mice and  is  associated  with  markers  of hippocampal neuronal damage identified by proteomics.  Society for Neuroscience 2014 Abstract

(3) Wang DS1, Zurek AA, Lecker I, Yu J, Abramian AM, Avramescu S, Davies PA, Moss SJ, Lu WY, Orser BA (2012)  Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors.  Cell Rep 2(3):488-96

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Supervisor: 
Dr R Langston, Prof L Williams & Prof J Lambert
Subject Area: 
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School: 
Start Date: 
Monday, September 4, 2017
Application Closing Date: 
Sunday, April 30, 2017