Publications by authors named "Chris Barkus"

13 Publications

  • Page 1 of 1

Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP.

Brain 2018 08;141(8):2457-2474

Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG UK.

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.
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http://dx.doi.org/10.1093/brain/awy159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061702PMC
August 2018

Pharmacological evidence that 5-HT receptor blockade selectively improves decision making when rewards are paired with audiovisual cues in a rat gambling task.

Psychopharmacology (Berl) 2017 Oct 21;234(20):3091-3104. Epub 2017 Jul 21.

Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.

Rationale: Adding reward-concurrent cues to a rat gambling task (rGT) increases risky choice. This cued version of the task may reflect an "addiction-like" cognitive process, more similar to human gambling than the uncued task. Serotonergic drugs that target 5-HT receptors alter mechanisms linked to impulse control. However, relatively little is known regarding the impact of such agents on either risky decision making, or the ability of conditioned stimuli to bias the choice process, despite potential relevance to addiction development and treatment.

Objectives: The aim of this study was to determine the effects of SB 242,084 and M100907, selective antagonists at the 5-HT and 5-HT receptors respectively, as well as the selective 5-HT receptor agonist Ro-60-0175, on performance of both cued and uncued versions of the rGT.

Results: SB 242,084 significantly and dose-dependently increased choice of the most optimal option in the cued rGT only, despite concurrently increasing impulsive responses made prematurely on both the cued and uncued rGT. M100907 and Ro-60-0175 did not alter risky decision making, but nevertheless produced the expected decrease in premature responses on both task variants.

Conclusions: These findings demonstrate that the 5-HT receptor-mediated regulation of risky decision making and motor impulsivity can be pharmacologically dissociated and further show that the presence of highly salient reward-paired cues critically alters the neurochemical regulation of the choice process. Importantly, these results suggest that 5-HT receptor antagonists may be of use in disrupting maladaptive patterns of decision making.
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http://dx.doi.org/10.1007/s00213-017-4696-4DOI Listing
October 2017

The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice.

Eur J Neurosci 2017 04 4;45(7):912-921. Epub 2017 Mar 4.

Department of Psychology, Durham University, Science Site, South Road, Durham, DH1 3LE, UK.

Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1 mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1 mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.
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http://dx.doi.org/10.1111/ejn.13539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396315PMC
April 2017

Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity.

Neuropsychopharmacology 2016 12 8;41(13):3060-3069. Epub 2016 Jul 8.

Department of Psychiatry, University of Oxford, Oxford, UK.

Catechol-O-methyltransferase (COMT) modulates dopamine levels in the prefrontal cortex. The human gene contains a polymorphism (ValMet) that alters enzyme activity and influences PFC function. It has also been linked with cognition and anxiety, but the findings are mixed. We therefore developed a novel mouse model of altered COMT activity. The human Met allele was introduced into the native mouse COMT gene to produce COMT-Met mice, which were compared with their wild-type littermates. The model proved highly specific: COMT-Met mice had reductions in COMT abundance and activity, compared with wild-type mice, explicitly in the absence of off-target changes in the expression of other genes. Despite robust alterations in dopamine metabolism, we found only subtle changes on certain cognitive tasks under baseline conditions (eg, increased spatial novelty preference in COMT-Met mice vs wild-type mice). However, genotype differences emerged after administration of the COMT inhibitor tolcapone: performance of wild-type mice, but not COMT-Met mice, was improved on the 5-choice serial reaction time task after tolcapone administration. There were no changes in anxiety-related behaviors in the tests that we used. Our findings are convergent with human studies of the ValMet polymorphism, and suggest that COMT's effects are most prominent when the dopamine system is challenged. Finally, they demonstrate the importance of considering COMT genotype when examining the therapeutic potential of COMT inhibitors.
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http://dx.doi.org/10.1038/npp.2016.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101554PMC
December 2016

Reduced sensitivity to both positive and negative reinforcement in mice over-expressing the 5-hydroxytryptamine transporter.

Eur J Neurosci 2014 Dec 4;40(12):3735-45. Epub 2014 Oct 4.

Department of Experimental Psychology, The University of Oxford, South Parks Road, Oxford, OX1 3UD, UK.

The 5-hydroxytryptamine (5-HT) transporter (5-HTT) is believed to play a key role in both normal and pathological psychological states. Much previous data suggest that the s allele of the polymorphic regulatory region of the 5-HTT gene promoter is associated with reduced 5-HTT expression and vulnerability to psychiatric disorders, including anxiety and depression. In comparison, the l allele, which increases 5-HTT expression, is generally considered protective. However, recent data link this allele to both abnormal 5-HT signalling and psychopathic traits. Here, we studied the processing of aversive and rewarding cues in transgenic mice that over-express the 5-HTT (5-HTTOE mice). Compared with wild-type mice, 5-HTTOE mice froze less in response to both a tone that had previously been paired with footshock, and the conditioning context. In addition, on a decision-making T-maze task, 5-HTTOE mice displayed reduced preference for a larger, delayed reward and increased preference for a smaller, immediate reward, suggesting increased impulsiveness compared with wild-type mice. However, further inspection of the data revealed that 5-HTTOE mice displayed a relative insensitivity to reward magnitude, irrespective of delay. In contrast, 5-HTTOE mice appeared normal on tests of spatial working and reference memory, which required an absolute choice between options associated with either reward or no reward. Overall, the present findings suggest that 5-HTT over-expression results in a reduced sensitivity to both positive and negative reinforcers. Thus, these data show that increased 5-HTT expression has some maladaptive effects, supporting recent suggestions that l allele homozygosity may be a potential risk factor for disabling psychiatric traits.
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http://dx.doi.org/10.1111/ejn.12744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737229PMC
December 2014

Hippocampal lesions can enhance discrimination learning despite normal sensitivity to interference from incidental information.

Hippocampus 2012 Jul 7;22(7):1553-66. Epub 2011 Dec 7.

Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.

Spatial properties of stimuli are sometimes encoded even when incidental to the demands of a particular learning task. Incidental encoding of spatial information may interfere with learning by (i) causing a failure to generalize learning between trials in which a cue is presented in different spatial locations and (ii) adding common spatial features to stimuli that predict different outcomes. Hippocampal lesions have been found to facilitate acquisition of certain tasks. This facilitation may occur because hippocampal lesions impair incidental encoding of spatial information that interferes with learning. To test this prediction mice with lesions of the hippocampus were trained on appetitive simple simultaneous discrimination tasks using inserts in the goal arms of a T-maze. It was found that hippocampal lesioned mice were facilitated at learning the discriminations, but they were sensitive to changes in spatial information in a manner that was similar to control mice. In a second experiment it was found that both control and hippocampal lesioned mice showed equivalent incidental encoding of egocentric spatial properties of the inserts, but both groups did not encode the allocentric information. These results demonstrate that mice show incidental encoding of egocentric spatial information that decreases the ability to solve simultaneous discrimination tasks. The normal egocentric spatial encoding in hippocampal lesioned mice contradicts theories of hippocampal function that suggest that the hippocampus is necessary for incidental learning per se, or is required for modulating stimulus representations based on the relevancy of information. The facilitated learning suggests that the hippocampal lesions can enhance learning of the same qualitative information as acquired by control mice.
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http://dx.doi.org/10.1002/hipo.20995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506972PMC
July 2012

Do GluA1 knockout mice exhibit behavioral abnormalities relevant to the negative or cognitive symptoms of schizophrenia and schizoaffective disorder?

Neuropharmacology 2012 Mar 15;62(3):1263-72. Epub 2011 Jun 15.

Department of Experimental Psychology, South Parks Road, University of Oxford, UK.

The glutamate system has been strongly implicated in the pathophysiology of psychotic illnesses, including schizophrenia and schizoaffective disorder. We recently found that knockout (KO) mice lacking the AMPA GluA1 subunit displayed behavioral abnormalities relevant to some of the positive symptoms of these disorders. Here we phenotyped GluA1 KO mice for behavioral phenotypes pertinent to negative and cognitive/executive symptoms. GluA1 KO mice were tested for conspecific social interactions, the acquisition and extinction of an operant response for food-reward, operant-based pairwise visual discrimination and reversal learning, and impulsive choice in a delay-based cost/benefit decision-making T-maze task. Results showed that GluA1 KO mice engaged in less social interaction than wildtype (WT) controls when tested in a non-habituated, novel environment, but, conversely, displayed more social interaction in a well habituated, familiar environment. GluA1 KO mice were faster to acquire an operant stimulus-response for food reward than WT and were subsequently slower to extinguish the response. Genotypes showed similar pairwise discrimination learning and reversal, although GluA1 KO mice made fewer errors during early reversal. GluA1 KO mice also displayed increased impulsive choice, being less inclined to choose a delayed, larger reward when given a choice between this and a smaller, immediate reward, compared to WT mice. Finally, sucrose preference did not differ between genotypes. Collectively, these data add to the growing evidence that GluA1 KO mice display at least some phenotypic abnormalities mimicking those found in schizophrenia/schizoaffective disorder. Although these mice, like any other single mutant line, are unlikely to model the entire disease, they may nevertheless provide a useful tool for studying the role of GluA1 in certain aspects of the pathophysiology of major psychotic illness.
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http://dx.doi.org/10.1016/j.neuropharm.2011.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208051PMC
March 2012

Deletion of the GluA1 AMPA receptor subunit impairs recency-dependent object recognition memory.

Learn Mem 2011 4;18(3):181-90. Epub 2011 Mar 4.

Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, United Kingdom.

Deletion of the GluA1 AMPA receptor subunit impairs short-term spatial recognition memory. It has been suggested that short-term recognition depends upon memory caused by the recent presentation of a stimulus that is independent of contextual-retrieval processes. The aim of the present set of experiments was to test whether the role of GluA1 extends to nonspatial recognition memory. Wild-type and GluA1 knockout mice were tested on the standard object recognition task and a context-independent recognition task that required recency-dependent memory. In a first set of experiments it was found that GluA1 deletion failed to impair performance on either of the object recognition or recency-dependent tasks. However, GluA1 knockout mice displayed increased levels of exploration of the objects in both the sample and test phases compared to controls. In contrast, when the time that GluA1 knockout mice spent exploring the objects was yoked to control mice during the sample phase, it was found that GluA1 deletion now impaired performance on both the object recognition and the recency-dependent tasks. GluA1 deletion failed to impair performance on a context-dependent recognition task regardless of whether object exposure in knockout mice was yoked to controls or not. These results demonstrate that GluA1 is necessary for nonspatial as well as spatial recognition memory and plays an important role in recency-dependent memory processes.
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http://dx.doi.org/10.1101/lm.2083411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056514PMC
July 2011

Auditory false perceptions are mediated by psychosis risk factors.

Cogn Neuropsychiatry 2011 25;16(4):289-302. Epub 2010 Nov 25.

a University of Wollongong , New South Wales , Australia.

Introduction: Auditory hallucinations exist in psychotic disorders as well as the general population. Proneness to hallucinations, as measured by positive schizotypy, predicts false perceptions during an auditory signal detection task (Barkus, Stirling, Hopkins, McKie, & Lewis, 2007). Our aim was to replicate this result and extend it by examining effects of age and sex, both important demographic predictors of psychosis.

Method: A sample of 76 healthy volunteers split into 15-17 years (n=46) and 19 years plus (n=30) underwent a signal detection task designed to detect propensity towards false perceptions under ambiguous auditory conditions. Scores on the Unusual Experiences subscale (UE) of the O-LIFE schizotypy scale, IQ, and a measure of working memory were also assessed.

Results: We replicated our initial finding (Barkus et al., 2007): High scores on positive schizotypy were associated with false perceptions. Younger participants who scored highly on positive schizotypy reported significantly more false perceptions compared to other groups (p=.04). Older participants who had had an imaginary friend reported more false perceptions during the signal detection task (p<.01).

Conclusions: Younger participants seem most vulnerable to the effects of positive schizotypal traits in terms of a signal detection deficit that underlies auditory hallucinations. Schizotypy may have greatest impact closer to the risk period for development of psychotic disorders.
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http://dx.doi.org/10.1080/13546805.2010.530472DOI Listing
September 2014

Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder?

Neurobiol Dis 2010 Dec 8;40(3):608-21. Epub 2010 Aug 8.

Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852-9411, USA.

Glutamatergic dysfunction is strongly implicated in schizophrenia and mood disorders. GluA1 knockout (KO) mice display schizophrenia- and depression-related abnormalities. Here, we asked whether GluA1 KO show mania-related abnormalities. KO were tested for behavior in approach/avoid conflict tests, responses to repeated forced swim exposure, and locomotor responses under stress and after psychostimulant treatment. The effects of rapid dopamine depletion and treatment with lithium or a GSK-3β inhibitor (SB216763) on KO locomotor hyperactivity were tested. Results showed that KO exhibited novelty- and stress-induced locomotor hyperactivity, reduced forced swim immobility and alterations in approach/avoid conflict tests. Psychostimulant treatment and dopamine depletion exacerbated KO locomotor hyperactivity. Lithium, but not SB216763, treatment normalized KO anxiety-related behavior and partially reversed hyperlocomotor behavior, and also reversed elevated prefrontal cortex levels of phospho-MARCKS and phospho-neuromodulin. Collectively, these findings demonstrate mania-related abnormalities in GluA1 KO and, combined with previous findings, suggest this mutant may provide a novel model of features of schizoaffective disorder.
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http://dx.doi.org/10.1016/j.nbd.2010.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955784PMC
December 2010

Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium.

Neurobiol Aging 2012 Mar 14;33(3):603-616.e3. Epub 2010 May 14.

Trinity College Institute of Neuroscience, School of Biochemistry & Immunology, Trinity College Dublin, Dublin, Ireland.

Delirium is an acute, severe neuropsychiatric syndrome, characterized by cognitive deficits, that is highly prevalent in aging and dementia and is frequently precipitated by peripheral infections. Delirium is poorly understood and the lack of biologically relevant animal models has limited basic research. Here we hypothesized that synaptic loss and accompanying microglial priming during chronic neurodegeneration in the ME7 mouse model of prion disease predisposes these animals to acute dysfunction in the region of prior pathology upon systemic inflammatory activation. Lipopolysaccharide (LPS; 100 μg/kg) induced acute and transient working memory deficits in ME7 animals on a novel T-maze task, but did not do so in normal animals. LPS-treated ME7 animals showed heightened and prolonged transcription of inflammatory mediators in the central nervous system (CNS), compared with LPS-treated normal animals, despite having equivalent levels of circulating cytokines. The demonstration that prior synaptic loss and microglial priming are predisposing factors for acute cognitive impairments induced by systemic inflammation suggests an important animal model with which to study aspects of delirium during dementia.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200140PMC
March 2012

Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks.

Neuron 2008 Dec;60(5):846-60

Department of Clinical Neurobiology, University of Heidelberg, D-69120 Heidelberg, Germany.

Controversy revolves around the differential contribution of NR2A- and NR2B-containing NMDA receptors, which coexist in principal forebrain neurons, to synaptic plasticity and learning in the adult brain. Here, we report genetically modified mice in which the NR2B subunit is selectively ablated in principal neurons of the entire postnatal forebrain or only the hippocampus. NR2B ablation resulted in smaller NMDA receptor-mediated EPSCs with accelerated decay kinetics, as recorded in CA1 pyramidal cells. CA3-to-CA1 field LTP remained largely unaltered, although a pairing protocol revealed decreased NMDA receptor-mediated charge transfer and reduced cellular LTP. Mice lacking NR2B in the forebrain were impaired on a range of memory tasks, presenting both spatial and nonspatial phenotypes. In contrast, hippocampus-specific NR2B ablation spared hippocampus-dependent, hidden-platform water maze performance but induced a selective, short-term, spatial working memory deficit for recently visited places. Thus, both hippocampal and extra-hippocampal NR2B containing NMDA receptors critically contribute to spatial performance.
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http://dx.doi.org/10.1016/j.neuron.2008.09.039DOI Listing
December 2008