-
[show abstract]
[hide abstract]
ABSTRACT: Cannabis use confers a two-fold increase in risk for psychosis, with adolescent use conferring an even greater risk. A high-low activity polymorphism in catechol-O-methyltransferase (COMT), a gene encoding the COMT enzyme involved in dopamine clearance in the brain, may interact with adolescent cannabis exposure to increase risk for schizophrenia. The impact of such an interaction on central neurotransmitter pathways implicated in schizophrenia is unknown. Male mice with knockout of the COMT gene were treated chronically with delta-9-tetrahydrocannabinol (THC) during adolescence (postnatal day 32-52). We measured the size and density of GABAergic cells and the protein expression of cannabinoid receptor 1 (CB1R) in the prefrontal cortex (PFC) and hippocampus (HPC) in knockout mice relative to heterozygous mutants and wild-type controls. Size and density of dopaminergic neurons was also assessed in the ventral tegmental area (VTA) across the genotypes. COMT genotype × THC treatment interactions were observed for: (1) dopaminergic cell size in the VTA, (2) CB1R protein expression in the HPC, and (3) parvalbumin (PV) cell size in the PFC. No effects of adolescent THC treatment were observed for PV and dopaminergic cell density across the COMT genotypes. COMT genotype modulates the effects of chronic THC administration during adolescence on indices of neurotransmitter function in the brain. These findings illuminate how COMT deletion and adolescent cannabis use can interact to modulate the function of neurotransmitters systems implicated in schizophrenia.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2012; 37(7):1773-83. · 6.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Schizophrenia is characterised by a multifactorial aetiology that involves genetic liability interacting with epigenetic and environmental factors to increase risk for developing the disorder. A consensus view is that the genetic component involves several common risk alleles of small effect and/or rare but penetrant copy number variations. Furthermore, there is increasing evidence for broader, overlapping genetic-phenotypic relationships in psychosis; for example, the same susceptibility genes also confer risk for bipolar disorder. Phenotypic characterisation of genetic models of candidate risk genes and/or putative pathophysiological processes implicated in schizophrenia, as well as examination of epidemiologically relevant gene × environment interactions in these models, can illuminate molecular and pathobiological mechanisms involved in schizophrenia. The present chapter outlines both the evidence from phenotypic studies in mutant mouse models related to schizophrenia and recently described mutant models addressing such gene × environment interactions. Emphasis is placed on evaluating the extent to which mutant phenotypes recapitulate the totality of the disease phenotype or model selective endophenotypes. We also discuss new developments and trends in relation to the functional genomics of psychosis which might help to inform on the construct validity of mutant models of schizophrenia and highlight methodological challenges in phenotypic evaluation that relate to such models.
Current topics in behavioral neurosciences. 02/2012; 12:209-50.
-
[show abstract]
[hide abstract]
ABSTRACT: In this review we consider the application of mutant mouse phenotypes to the study of psychotic illness in general and schizophrenia in particular, as they relate to behavioral, psychopharmacological, and cellular phenotypes of putative import for antipsychotic drug development. Mutant models appear to be heuristic at two main levels; firstly, by indicating the functional roles of neuronal components thought to be of relevance to the putative pathobiology of psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those neuronal components; secondly, by indicating the functional roles of genes associated with risk for psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those risk genes. We focus initially on models of dopaminergic and glutamatergic dysfunction. Then, we consider advances in the genetics of schizophrenia and mutant models relating to replicable risk genes. Lastly, we extend this discussion by exemplifying two new variant approaches in mutant mice that may serve as prototypes for advancing antipsychotic drug development. There is continuing need not only to address numerous technical challenges but also to develop more "real-world" paradigms that reflect the milieu of gene × environment and gene × gene interactions that characterize psychotic illness and its response to antipsychotic drugs.
Handbook of experimental pharmacology 01/2012;
-
[show abstract]
[hide abstract]
ABSTRACT: Catechol-O-methyltransferase, an enzyme involved in regulating brain catecholamine levels, has been implicated in anxiety, pain and/or stress responsivity. Elements of this putative association remain unclarified, notably whether: (a) COMT variation modulates responses to acute and/or chronic stress equally; (b) acute pharmacological inhibition of COMT produces comparable effects on anxiety to that observed after deletion of the COMT gene; (c) COMT genotype modulates action of anxiolytic drugs. We aimed to further investigate the relationship between reduced COMT function, anxiety and stress responsivity in mice. To compare the effect of acute vs. chronic restraint stress in female COMT KO vs. WT mice, serum corticosterone and cytokine concentrations were measured [Experiment 1]. Sensitivity to the benzodiazepines midazolam and chlordiazepoxide in the light-dark test was assessed in female COMT KO vs. WT mice [Experiment 2]. Effects of acute administration of the COMT inhibitor tolcapone, and of these same benzodiazepines thereon, in the light-dark test were assessed in female C57BL/6 mice [Experiment 3]. COMT KO mice demonstrated an increased corticosterone response to acute but not chronic stress, and a modified cytokine profile after chronic, but not acute stress. COMT KO mice showed increased anxiety, but benzodiazepine sensitivity was affected by COMT genotype. Whilst tolcapone had no effect on light/dark performance in C57BL6/J mice it decreased benzodiazepine sensitivity. These data elaborate earlier findings of increased anxiety in female COMT KO mice and also clarify a role for COMT in modulating stress-related hormonal and immune parameters in a manner that depends on chronicity of the stressor.
Behavioural brain research 12/2011; 228(2):351-8. · 3.22 Impact Factor
-
Colm M P O'Tuathaigh,
Gerard Clarke,
Jeremy Walsh,
Lieve Desbonnet,
Emilie Petit,
Claire O'Leary,
Orna Tighe,
Niamh Clarke,
Maria Karayiorgou,
Joseph A Gogos,
Ted G Dinan,
John F Cryan,
John L Waddington
[show abstract]
[hide abstract]
ABSTRACT: Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.
The International Journal of Neuropsychopharmacology 11/2011; 15(9):1331-42. · 4.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Schizophrenia is a heritable disorder that may involve several common genes of small effect and/or rare copy number variation, with phenotypic heterogeneity across patients. Furthermore, any boundaries vis-à-vis other psychotic disorders are far from clear. Consequently, identification of informative animal models for this disorder, which typically relate to pharmacological and putative pathophysiological processes of uncertain validity, faces considerable challenges. In juxtaposition, the majority of mutant models for schizophrenia relate to the functional roles of a diverse set of genes associated with risk for the disorder or with such putative pathophysiological processes. This chapter seeks to outline the evidence from phenotypic studies in mutant models related to schizophrenia. These have commonly assessed the degree to which mutation of a schizophrenia-related gene is associated with the expression of several aspects of the schizophrenia phenotype or more circumscribed, schizophrenia-related endophenotypes; typically, they place specific emphasis on positive and negative symptoms and cognitive deficits, and extend to structural and other pathological features. We first consider the primary technological approaches to the generation of such mutants, to include their relative merits and demerits, and then highlight the diverse phenotypic approaches that have been developed for their assessment. The chapter then considers the application of mutant phenotypes to study pathobiological and pharmacological mechanisms thought to be relevant for schizophrenia, particularly in terms of dopaminergic and glutamatergic dysfunction, and to an increasing range of candidate susceptibility genes and copy number variants. Finally, we discuss several pertinent issues and challenges within the field which relate to both phenotypic evaluation and a growing appreciation of the functional genomics of schizophrenia and the involvement of gene × environment interactions.
Current topics in behavioral neurosciences. 02/2011; 7:87-119.
-
[show abstract]
[hide abstract]
ABSTRACT: Generation and regulation of orofacial movements involve complex mechanisms that include primary roles not only for dopamine but also the amino acid neurotransmitters γ-aminobutyric acid (GABA) and glutamate. However, the roles of individual GABA and glutamate receptor subtypes, subunits and associated processes are unclear. Here we outline studies of motor function in mutant mice with "knockout" of GABA and glutamate receptor subtypes. We then review systematic studies of orofacial movements in mutants with (i) "Knockout" of phospholipase C-related catalytically inactive protein (PRIP), which regulates cell surface expression of GABA(A) receptors containing a γ2 subunit, and: (ii) Heterozygous deletion of neuregulin-1 which, inter alia, regulates glutamate receptor-mediated processes. Each of GABAergic and glutamatergic sytems regulate specific topographies of orofacial movement both individually and via interactions with dopaminergic processes.
International Review of Neurobiology 01/2011; 97:61-75. · 2.35 Impact Factor
-
Colm M P O'Tuathaigh,
Magdalena Hryniewiecka,
Aine Behan,
Orna Tighe,
Catherine Coughlan,
Lieve Desbonnet,
Mary Cannon,
Maria Karayiorgou,
Joseph A Gogos,
David R Cotter,
John L Waddington
[show abstract]
[hide abstract]
ABSTRACT: Cannabis use confers a two-fold increase in the risk for psychosis, with adolescent use conferring even greater risk. A high-low activity catechol-O-methyltransferase (COMT) polymorphism may modulate the effects of adolescent Δ-9-tetrahydrocannabinol (THC) exposure on the risk for adult psychosis. Mice with knockout of the COMT gene were treated chronically with THC (4.0 and 8.0 mg/kg over 20 days) during either adolescence (postnatal days (PDs) 32-52) or adulthood (PDs 70-90). The effects of THC exposure were then assessed in adulthood across behavioral phenotypes relevant for psychosis: exploratory activity, spatial working memory (spontaneous and delayed alternation), object recognition memory, social interaction (sociability and social novelty preference), and anxiety (elevated plus maze). Adolescent THC administration induced a larger increase in exploratory activity, greater impairment in spatial working memory, and a stronger anti-anxiety effect in COMT knockouts than in wild types, primarily among males. No such effects of selective adolescent THC administration were evident for other behaviors. Both object recognition memory and social novelty preference were disrupted by either adolescent or adult THC administration, independent of genotype. The COMT genotype exerts specific modulation of responsivity to chronic THC administration during adolescence in terms of exploratory activity, spatial working memory, and anxiety. These findings illuminate the interaction between genes and adverse environmental exposures over a particular stage of development in the expression of the psychosis phenotype.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2010; 35(11):2262-73. · 6.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present series of review articles seeks to elaborate how current findings in mutant mice may inform on the relationship between candidate genes and individual psychopathological and pathobiological aspects of schizophrenia. Each of the authors focuses on an overlapping selection of both well-characterized and emergent candidate genes, as identified through association and linkage studies and/or via their involvement in putative pathophysiological mechanisms, particularly those relating to dopaminergic and glutamatergic processes.
Schizophrenia Bulletin 02/2010; 36(2):243-5. · 8.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Negative symptoms encompass diminution in emotional expression and motivation, some of which relate to human attributes that may not be accessible readily in animals. Additionally, their refractoriness to treatment precludes therapeutic validation of putative models. This review considers critically the application of mutant mouse models to the study of the pathobiology of negative symptoms. It focuses on 4 main approaches: genes related to the pathobiology of schizophrenia, genes associated with risk for schizophrenia, neurodevelopmental-synaptic genes, and variant approaches from other areas of neurobiology. Despite rapid advances over the past several years, it is clear that we continue to face substantive challenges in applying mutant models to better understand the pathobiology of negative symptoms: the majority of evidence relates to impairments in social behavior, with only limited data relating to anhedonia and negligible data concerning avolition and other features; even for the most widely examined feature, social behavior, studies have used diverse assessments thereof; modelling must proceed in cognizance of increasing evidence that genes and pathobiologies implicated in schizophrenia overlap with other psychotic disorders, particularly bipolar disorder. Despite the caveats and challenges, several mutant lines evidence a phenotype for at least one index of social behavior. Though this may suggest superficially some shared relationship to negative symptoms, it is not yet possible to specify either the scope or the pathobiology of that relationship for any given gene. The breadth and depth of ongoing studies in mutants hold the prospect of addressing these shortcomings.
Schizophrenia Bulletin 11/2009; 36(2):271-88. · 8.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Schizophrenia is a complex, heritable psychotic disorder in which numerous genes and environmental adversities appear to interact in determining disease phenotype. In addition to genes regulating putative pathophysiological mechanisms, a new generation of molecular studies has indicated numerous candidate genes to be associated with risk for schizophrenia. The present review focuses on studies in mice mutant for genes associated with putative pathophysiological mechanisms and candidate risk genes for the disorder. It seeks to evaluate the extent to which each mutation of a schizophrenia-related gene accurately models multiple aspects of the schizophrenia phenotype or more circumscribed, distinct endophenotypes in terms of psychopathology and pathobiology; in doing so, it places particular emphasis on positive symptoms, negative symptoms and cognitive dysfunction. To further this goal, it juxtaposes continually evolving mutant genomics with emergent clinical genomic studies. Opportunities and challenges associated with the use of such mutants, including diagnostic specificity and the translational barrier associated with modelling schizophrenia, are discussed. The potential value of genetic models for exploring gene-gene and gene-environment interactions relating to schizophrenia is highlighted. Elucidation of the contribution of genetic variation to specific symptom clusters and underlying aspects of pathobiology will have important implications for identifying treatments that target distinct domains of psychopathology and dysfunction on an individual patient basis.
Brain research bulletin 10/2009; 83(3-4):162-76. · 2.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Schizophrenia is a highly complex and heritable psychiatric disorder in which multiple genes and environmental factors interact to cause the schizophrenia phenotype. A new generation of molecular studies has yielded numerous candidate genes with a putative role in risk for schizophrenia, whereas other genes regulate putative pathophysiological mechanisms. Mutant mice having either deletion (knockout) or insertion (knockin/transgenesis) of schizophrenia risk genes now allow the functional role of these genes to be investigated. In the present mini-review, we outline the advantages and limitations of various approaches to phenotypic assessment of mutant mouse models, including ethologically based methods. Thereafter, we consider recent findings, with a particular focus on, first, dopaminergic and glutamatergic pathophysiological models and, secondly, putative roles for DISC1 (disrupted in schizophrenia 1) and NRG1 (neuregulin 1) as susceptibility genes for schizophrenia. Finally, we identify current challenges associated with the use of genetic mutant models and highlight their potential value for exploring gene-gene and gene-environment interactions in relation to schizophrenia.
Biochemical Society Transactions 03/2009; 37(Pt 1):308-12. · 3.71 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Latent inhibition (LI) is reduced learning to a stimulus that has previously been experienced without consequence. It is an important model of abnormal allocation of salience to irrelevant information in patients with schizophrenia. In rodents LI is abolished by psychotomimetic drugs and in experimental conditions where LI is low in controls, its expression is enhanced by antipsychotic drugs with activity at dopamine (DA) receptors. It is however unclear what the independent contributions of DA receptor subtypes are to these effects. This study therefore examined LI in congenic DA D1 and D2 receptor knockout (D1 KO and D2 KO) mice. Conditioned suppression of drinking was used as the measure of learning in the LI procedure. Both male and female DA D2 KO mice showed clear enhancement of LI reproducing antipsychotic drug effects in the model. Unexpectedly, enhancement was also seen in D1 KO female mice but not in D1 KO male mice. This sex-specific pattern was not replicated in locomotor or motor coordination tasks nor in the effect of DA KOs on baseline learning in control groups indicating some specificity of the effect to LI. These data suggest that the dopaminergic mechanism underlying LI potentiation and possibly antipsychotic action may differ between the sexes, being mediated by D2 receptors in males but by both D1 and D2 receptors in females. These data suggest that the DA D1 receptor may prove an important target for understanding sex differences in the mechanisms of action of antipsychotic drugs and in the aetiology of aberrant salience allocation in schizophrenia.
The International Journal of Neuropsychopharmacology 12/2008; 12(3):403-14. · 4.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Clinical genetic studies have implicated neuregulin-1 [NRG1] as a leading susceptibility gene for schizophrenia. NRG1 is known to play a significant role in the developing brain, which is consistent with the prevailing neurodevelopmental model of schizophrenia. Thus, the emotional and social phenotype of adult mice with heterozygous 'knockout' of transmembrane [TM]-domain NRG1 was examined further in both sexes. Emotional/anxiety-related behaviour was assessed using the elevated plus-maze and the light-dark test. Social behaviour was examined in terms of dyadic interactions between NRG1 mutants and an unfamiliar C57BL6 conspecific in a novel environment. There was no effect of NRG1 genotype on performance in either test of emotionality/anxiety. However, previous reports of hyperactivity in NRG1 mutants were confirmed in both paradigms. In the test of social interaction, aggressive following was increased in NRG1 mutants of both sexes, together with an increase in walkovers in female mutants. These findings elaborate the specificity of the NRG1 phenotype for the social rather than the emotional/anxiety-related domain. They indicate that NRG1 is involved in the regulation of reciprocal social interaction behaviour and thus suggest a putative role for NRG1 in a schizophrenia-related endophenotype.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2008; 32(2):462-6. · 3.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This article summarizes the rationale, methods, and results of gene discovery programs in schizophrenia research and describes functional methods of investigating potential candidate genes. It focuses next on the most prominent current candidate genes and describes (1) evidence for their association with schizophrenia and research into the function of each gene; (2) investigation of the clinical phenotypes and endophenotypes associated with each gene, at the levels of psychopathologic, neurocognitive, electrophysiologic, neuroimaging, and neuropathologic findings; and (3) research into the ethologic, cognitive, social, and psychopharmacologic phenotype of mutants with targeted deletion of each gene. It examines gene-gene and gene-environment interactions. Finally, it looks at future directions for research.
The Psychiatric clinics of North America 10/2007; 30(3):365-99. · 1.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A wealth of evidence indicates that schizophrenia is heritable. However, the genetic mechanisms involved are poorly understood. Furthermore, it may be that genes conferring susceptibility interact with one another and with non-genetic factors to modulate risk status and/or the expression of symptoms. Genome-wide scanning and the mapping of several regions linked with risk for schizophrenia have led to the identification of several putative susceptibility genes including neuregulin-1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signalling 4 (RGS4), catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH) and disrupted-in-schizophrenia 1 (DISC1). Genetic animal models involving targeted mutation via gene knockout or transgenesis have the potential to inform on the role of a given susceptibility gene on the development and behaviour of the whole organism and on whether disruption of gene function is associated with schizophrenia-related structural and functional deficits. This review focuses on data regarding the behavioural phenotype of mice mutant for schizophrenia susceptibility genes identified by positional candidate analysis and the study of chromosomal abnormalities. We also consider methodological issues that are likely to influence phenotypic effects, as well as the limitations associated with existing molecular techniques.
Neuroscience & Biobehavioral Reviews 02/2007; 31(1):60-78. · 8.65 Impact Factor
