Dopaminergic involvement in stimulus selection : a behavioural study

People with schizophrenia show deficits in the inhibitory processes controlling stimulus selection. Overshadowing and the Kamin blocking effect provide examples of stimulus selection. Overshadowing refers to the phenomenon whereby greater learning accrues to the more salient stimulus of a compound presentation. Kamin blocking occurs when prior learning to a single stimulus in stage 1 disrupts learning to an added stimulus in stage 2, when both stimuli are presented in compound. Both paradigms measure the ability to select relevant and deselect irrelevant information from the stimulus environment, and are dependent upon cognitive processes hypothesised to be disrupted in schizophrenic patients. The study of the neural basis of such stimulus phenomena provides a putative model with construct validity for the information processing deficits seen in schizophrenia. A disturbance in central dopaminergic activity is thought to underlie the cognitive deficits of schizophrenia. In the present study, the effect of dopaminergic manipulations on Kamin blocking and overshadowing was assessed in the rat.;The indirect dopamine agonist d-amphetamine (1.0 mg/kg, i.p.) disrupted Kamin blocking when administered at stage 2 conditioning. Amphetamine also abolished overshadowing when given at conditioning. It was concluded that amphetamine effects in both paradigms may consist of a selective increase in learning to the less salient stimulus.;The DA antagonist haloperidol (0.2 mg/kg, i.p.) failed to reverse the attenuating effects of amphetamine (1.0 mg/kg i.p.) on overshadowing. However, haloperidol (0.2 mg/kg & 0.5 mg/kg, i.p.) successfully reversed amphetamine-induced hyperlocomotion. Neither the selective D2 receptor antagonist raclopride (0.5 mg/kg, i.p.) nor the selective D2 receptor antagonist sulpiride (50 & 100 mg/kg, i.p.) restored overshadowing in amphetamine - treated animals.;SCH23390 (0.05 mg/kg, i.p.), the selective D1 receptor antagonist, restored overshadowing in amphetamine - treated rats. The D1 receptor agonist SKF 38393 (5 mg/kg i.p.) disrupted overshadowing in a manner similar to that observed following amphetamine treatment

Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia

Human genetic studies have shown that neuregulin 1 (NRG1) is a potential susceptibility gene for schizophrenia. Nrg1 influences various neurodevelopmental processes, which are potentially related to schizophrenia. The neurodevelopmental theory of schizophrenia suggests that interactions between genetic and environmental factors are responsible for biochemical alterations leading to schizophrenia. To investigate these interactions and to match experimental design with the pathophysiology of schizophrenia, we applied a comprehensive behavioural phenotyping strategy for motor activity, exploration and anxiety in a heterozygous Nrg1 transmembrane domain mutant mouse model (Nrg1 HET) using different housing conditions and age groups. We observed a locomotion- and exploration-related hyperactive phenotype in Nrg1 HETs. Increased age had a locomotion- and exploration-inhibiting effect, which was significantly attenuated in mutant mice. Environmental enrichment (EE) had a stimulating influence on locomotion and exploration. The impact of EE was more pronounced in Nrg1 hypomorphs. Our study also showed a moderate task-specific anxiolytic-like phenotype for Nrg1 HETs, which was influenced by external factors. The behavioural phenotype detected in heterozygous Nrg1 mutant mice is not specific to schizophrenia per se, but the increased sensitivity of mutant mice to exogenous factors is consistent with the pathophysiology of schizophrenia and the neurodevelopmental theory. Our findings reinforce the importance of carefully controlling experimental designs for external factors and of comprehensive, integrative phenotyping strategies. Thus, Nrg1 HETs may, in combination with other genetic and drug models, help to clarify pathophysiological mechanisms behind schizophrenia

Modeling the Positive Symptoms of Schizophrenia in Genetically Modified Mice: Pharmacology and Methodology Aspects

In recent years, there have been huge advances in the use of genetically modified mice to study pathophysiological mechanisms involved in schizophrenia. This has allowed rapid progress in our understanding of the role of several proposed gene mechanisms in schizophrenia, and yet this research has also revealed how much still remains unresolved. Behavioral studies in genetically modified mice are reviewed with special emphasis on modeling psychotic-like behavior. I will particularly focus on observations on locomotor hyperactivity and disruptions of prepulse inhibition (PPI). Recommendations are included to address pharmacological and methodological aspects in future studies. Mouse models of dopaminergic and glutamatergic dysfunction are then discussed, reflecting the most important and widely studied neurotransmitter systems in schizophrenia. Subsequently, psychosis-like behavior in mice with modifications in the most widely studied schizophrenia susceptibility genes is reviewed. Taken together, the available studies reveal a wealth of available data which have already provided crucial new insight and mechanistic clues which could lead to new treatments or even prevention strategies for schizophrenia

Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction

We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein–coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology