GABAergic interneurones and schizophrenia

Lead Research Organisation: University of Aberdeen
Department Name: Biomedical Sciences


Schizophrenia badly affects those that suffer from it. Well known symptoms include hearing voices or other hallucinations. These symptoms can be treated, to some extent, with existing medicines. But there are other problems: patients have disorganized, slow thinking; they have poor concentration, and poor memory. This means that patients with schizophrenia often cannot organize their everyday lives. Drugs that would improve the thinking and memory abilities of patients are much needed. To invent new drugs requires understanding the brain circuits needed for thinking and memory. We and other researchers believe that a specific type of brain cell has gone wrong in schizophrenia, and that these cells are not wired up properly. This type of cell usually says no to other cells. But more than just saying no, these are master command cells; they say no to many thousands of other brain cells all at once. Patients with schizophrenia may have faulty command cells that do not properly say no. Using genetically altered mice, we plan to model and study the master brain cells and learn how they work. We hope that our research will one day lead to better drugs that help patients improve their memory and thinking.

Technical Summary

Schizophrenia affects approximately 1% of the population. Patients suffer from psychosis (delusions, perceptual disturbances and hallucinations) and disruptions in cognitive functions: attention, working memory and planned behaviour. Medication reduces the psychosis but not the cognitive impairments; unfortunately, it is the latter that most hinder daily life and their extent best predicts long-term outcome. A central hypothesis is that cognitive processing is reflected by variations in the external electrical field ? e.g. gamma (30-90Hz) oscillations. Cognitive theories predict that oscillations provide reference signals for representing, processing and storing information by transiently synchronized groups of neurons. In patients suffering from schizophrenia, gamma is reduced, and may underlie the cognitive deficits. To develop targeted treatments for the cognitive defects will require greater knowledge of the circuits that govern working memory (the ability to keep events ?in mind? for short time periods). In spite of our increasing knowledge about the ?wiring diagram? of the hippocampus and neocortex, little is known about the specific contributions that the diverse interneurone types make to behaviour. We propose to study unique models we have generated that would (1) inform on how gamma oscillations are regulated; (2) permit for the first time these oscillations to be reversibly and selectively manipulated to see if this correlates with behaviour (working memory); and (3) reveal if GABA-A receptor signalling shapes the establishment of this neuronal network during development. We would:
(A) functionally and selectively remove parvalbumin-expressing interneurons from local circuits. This will enable us to test if long-term malfunctions of this cell class produce and phenocopy the change in network activity found in schizophrenia. Will removal of parvalbumin cells impair working memory, defined as the cognitive process that stores and manipulates information relevant only for a short period of time during an experimental session?
(B) refine a new and original approach we have developed (the ?zolpidem method?) to dissect circuit components.
(C) use the ?zolpidem method? to selectively and reversibly increase GABAergic drive onto hippocampal and fronto-cortical parvalbumin-containing cells in vivo, and study the consequences to see if (i) gamma oscillations are reversibly decreased; and (ii) if this decrease can be correlated with poorer working memory.
(D) use a GABA-A receptor ?g2 knockdown? to analyse how GABA transmission affects the phenotype of GABAergic neurons in the neocortex.


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Baker R (2014) Altered activity in the central medial thalamus precedes changes in the neocortex during transitions into both sleep and propofol anesthesia. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Goetz T (2007) GABA(A) receptors: structure and function in the basal ganglia. in Progress in brain research

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McClure C (2011) Production and titering of recombinant adeno-associated viral vectors. in Journal of visualized experiments : JoVE

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Pang DS (2009) An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action. in Proceedings of the National Academy of Sciences of the United States of America

Description MRC Programme Grant G0901892
Amount £1,094,760 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2009 
End 10/2014
Description Wellcome Trust Investigator Awrad
Amount £1,000,000 (GBP)
Funding ID 107841/Z/15/Z 
Organisation Wellcome Trust 
Department Wellcome Trust Senior Investigator Award
Sector Private
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2015 
End 09/2021
Title AAV-flex switch tet toxin 
Description This is a gene which stops neurotransmission when activated by cre recombinase. It will be a useful reagent for cell-type selective analysis of gene circuitry (Murray et al., 2011 Nat Neurosci). 
Type Of Material Technology assay or reagent 
Year Produced 2011 
Provided To Others? Yes  
Impact in progress 
Title HDC-Cre 
Description Mouse line with Cre recombinase selectively expressed in cells that express histidine decarboxylase 
Type Of Material Technology assay or reagent 
Year Produced 2012 
Provided To Others? Yes  
Impact deposited at the JAX labs in 2013 
Title Plasmid deposits at Addgene 
Description A series of plasmids deposited at Addgene. these plasmids were used in two of our papers in 2015. Zhang et al. Nat Neurosci and Yu et al Neuron. 
Type Of Material Technology assay or reagent 
Year Produced 2016 
Provided To Others? Yes  
Impact The plasmids will be broadly useful to various neuroscientists. 
Title zolpidem method 
Description In mammals, identifying the contribution of specific neurons or networks to behavior is a key challenge. Here we describe an approach that facilitates this process by enabling the rapid modulation of synaptic inhibition in defined cell populations. Binding of zolpidem, a systemically active allosteric modulator that enhances the function of the GABA-A receptor, requires a phenylalanine residue (Phe77) in the gamma2 subunit. Mice in which this residue is changed to isoleucine are insensitive to zolpidem. By Cre recombinase-induced swapping of the gamma2 subunit (that is, exchanging Ile77 for Phe77), zolpidem sensitivity can be restored to GABA-A receptors in chosen cell types. We demonstrated the power of this method in the cerebellum, where zolpidem rapidly induces significant motor deficits when Purkinje cells are made uniquely sensitive to its action. This combined molecular and pharmacological technique has demonstrable advantages over targeted cell ablation and will be invaluable for investigating many neuronal circuits. Wulff P, Goetz T, Leppa E, Linden AM, Renzi M, Swinny JD, Vekovischeva OY, Sieghart W, Somogyi P, Korpi ER, Farrant M, Wisden W (2007) From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors. Nat Neurosci 10:923-929. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact The method, which involves mouse genetics, generated a lot of interest. 
Description BBSRC histamine 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution The team at MRC-LMB helped us win a BBSRC project grant
Collaborator Contribution They provided a specialist technique
Impact So far, it helped us win a BBSRC grant
Start Year 2013
Description MRC programme grant "Neuronal Pathways of Sleep and Anaesthesia" 
Organisation Imperial College London
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Our team at the South Kensington Campus of Imperial College London has a unique combination of expertise and experience. Franks' knowledge of anaesthetic mechanisms and physics background, Wisden's knowledge of molecular neuroscience and mouse genetics, and Brickley's experience of neuronal electrophysiology and ion channels form the core; in addition we have experienced chemists who work with us
Collaborator Contribution multidisciplinary inputs - hugely stimulating intellectual contributions and discussions, and knowledege of EEG receording and neurophsyiology
Impact Multidisciplinary collaboration. anaesthetic mechanisms and physics; molecular neuroscience and mouse genetics; neuronal electrophysiology; inh vivo recording
Start Year 2010
Description MRC project grant "Sleep Pathways and General Anaesthesia" 
Organisation Imperial College London
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We developed a novel mouse genetics method to manipulate the activity of specific subtypes of neuron. We developed potassium channel knockout mouse lines.
Collaborator Contribution It helped consolidate a long-term research grouping between myself, Prof. Nick Franks (Imperial College London) and Dr Stephen Brickley (Imperial College London)
Impact PMID: 17572671 [PubMed - indexed for MEDLINE] PMID: 19805135 [PubMed - indexed for MEDLINE]
Start Year 2006
Description Radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact see: The co PI on the grant, Dr Peer Wulff, was interviewed about the Wulff et al 2009 PNAS paper on Scottish BBC radio and in the local press.

enhanced public understanding and interest
Year(s) Of Engagement Activity 2009