J L Waddington

..Bipolar disorder and schizophrenia might reflect similar insult(s) acting over slightly differing time-frames or slightly differing insult(s) acting over a similar time-frame...

....

..Adversities operating over intrauterine life have been associated with risk of schizophrenia, but the biology of resultant developmental perturbation is poorly understood...

..As understanding of the pathobiology of schizophrenia increases, the challenge is to relate such measures to outcome at a functional level...

....

..It examines gene-gene and gene-environment interactions. Finally, it looks at future directions for research...

..Although increased mortality is one of the most consistent and accepted epidemiological findings in schizophrenia, a high rate of suicide appears unable to account fully for this burden which remains poorly understood...

..Furthermore, there are poorly understood methodological factors that contribute to inconsistent phenotypic findings between laboratories...

....

..The data suggest that catechol-O-methyltransferase and neuregulin-1 may influence, respectively, primarily cognitive and social endophenotypes of the overall schizophrenia syndrome...

..This methodology will allow the use of knockout mice to clarify the roles of individual dopamine receptor subtypes in their regulation...

..0mg/kg). These results indicate a differential contribution of NRG1 and DISC1 vis-à-vis COMT to the processing of thermal nociceptive stimuli and extend their phenotypic relationship to psychotic illness...

....

..These data indicate a subtle role for NRG1 in modulating several schizophrenia-relevant processes including the effects of psychotomimetic N-methyl-D-aspartate receptor antagonists...

..These data are consistent with behavioural primacy of a D1-like receptor other than D1A [or D1B] that is coupled to a transduction system other than/additional to adenylyl cyclase...

..It is being complemented by more systematic phenotypic characterisation at the level of behaviour and additional, molecular biologically-based approaches...

....

..This is discussed in the context of the functional role of the gene vis à vis a schizophrenia phenotype as well as the value of ethologically based approaches to behavioral phenotyping...

..These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia...

..Motor and cortical signs evidence state-like characteristics and vary with clinical course, while 'harder' signs evidence more static, trait-like characteristics in accordance with a neurodevelopmental basis...

..The aim was to examine the relationship between NSS and insight in a sample of 241 first-episode psychosis patients...

....

....

..We also consider methodological issues that are likely to influence phenotypic effects, as well as the limitations associated with existing molecular techniques...

..0% vs 13.5%; P=0.036). Interestingly, this refined 'at-risk' haplotype is positioned close to an EST cluster of unknown function (Hs.97362) within intron 1 of NRG1...

..Heterozygous COMT deletion is associated with a distinctive phenotype. This differs from that which we have reported previously for heterozygous deletion of the schizophrenia risk gene neuregulin-1...

..Genetic background appears to modulate critically the magnitude but not the general nature of the D(1A)-null phenotype, which may involve compensatory processes independent of other D(1)-like or D(2)-like receptors...

..Additionally, they indicate the involvement of phosphoinositide hydrolysis and D(5):D(2)-like interactions in regulating these processes...

..A role for D(3) receptors in inhibitory processes appeared topographically circumscribed and only when baseline levels of behaviour were low...

..Emphasis is also placed on the importance of studying gene x environment and gene x gene interactions, as well as addressing methodological issues related to genetic modelling and phenotyping strategies...

..The brain and face emerge in embryologic intimacy, such that in neurodevelopmental disorders, brain dysmorphogenesis is accompanied by facial dysmorphogenesis...

..Understanding the mechanistic bases of mitigation vs persistence of individual phenotypes in relation to neural adaptation consequent to cell loss may lead to novel therapeutic strategies for basal ganglia disorders...

..These studies elaborate a pleiotropic role of neuregulin-1 in development, plasticity and function, including sexual dimorphism, by defining the elemental, temporal and sex-specific characteristics of the neuregulin-1 mutant ethogram...

..The breadth and depth of ongoing studies in mutants hold the prospect of addressing these shortcomings...

..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...

....

..These findings illuminate the interaction between genes and adverse environmental exposures over a particular stage of development in the expression of the psychosis phenotype...

....

....

....

..Events over early fetal life may be an important determinant of sexually dimorphic covariance of anterior facial shape and asymmetry with aspects of cognition that involve the anterior brain...

..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...

..D2 receptors exert topographically specific regulation of orofacial movements in a manner distinct from their D1A counterparts, while D3 receptors exert only minor regulation of such movements...

..These studies identify novel functional roles for the D4 receptor that are distinct from those of closely related D2-like family members and involve interactions with their D1-like counterparts...

....

....

....

....

..For example, the seizure and vacuous chewing responses appear to involve dopamine D1-like receptors that stimulate adenylyl cyclase, while intense grooming involves those which do not...

....

..Critically, the present data indicate that phenotypic effects of a given gene deletion using an agonist acting on the system disrupted cannot be generalized to a corresponding antagonist, and vice versa...

..The most significant finding mapped to a micro-RNA, MIR-137, which may be involved in regulating the function of other schizophrenia and bipolar disorder susceptibility genes...

....

..This study examined concurrent associations and predictors at first indication of nonadherence to antipsychotic medication four years after a first episode of psychosis...

..Thus, interventions that shorten the duration of untreated psychosis (DUP) and arrest early deterioration may have long-term benefits...

..These findings indicate that D(1), and to a lesser extent D(5), receptor coupling to DARPP-32, ERK1/2 and glutamatergic signalling is involved in mediating the convulsant effects of SKF 83822...

..Four years later 18% had made a suicide attempt and 3% completed suicide. Suicide attempts prior to presentation were associated with a longer duration of untreated psychosis...

..The same haplotype is in excess in the Caucasian schizophrenia sample used by Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. This study provides further support for the contribution of RGS4 to schizophrenia susceptibility...

..No evidence was found to suggest an association between the DTNBP1 gene and schizophrenia in our sample. Possible reasons for these findings are discussed...

..9 points. CONCLUSIONS: This study extends the findings of short-term follow-up studies by confirming an association between duration of untreated psychosis and 'mid-term' outcome...

..We found no evidence to support the hypothesis that genetic variation at the APOL genes contributes to SZ susceptibility in our sample...

....

..Additionally, results obtained using SK&F 82958 as a probe for D1-like mechanisms should be treated with considerable caution until they are confirmed using other D1-like agonists...

..It would appear that as years of chronic, refractory illness accrue, psychomotor poverty becomes more sharply delineated and dominant within the overall structure of psychopathology, and its prominence is predicted enduringly by DUP...

..Gene expression data and association analyses in two Chinese samples implicate chitinase 3-like 1 (CHI3L1), a cellular survival gene, in schizophrenia susceptibility...

..In the absence of agonists and antagonists evidencing appropriate selectivities, individual and interactive properties of D(1) and D(3) dopamine receptors would be illuminated most powerfully by their co-deletion...

..Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci...

..Under these conditions, small area variations in bipolar disorder may be limited...

..Patients were diagnosed by Structured Clinical Interview for DSM (SCID) and we determined the DUP using the Beiser Scale. The DUP of the 240 participants did not differ significantly between study periods...

..Upregulated dopamine D2-like binding and enkephalin in D1(-/-) mice may be due to decreased dopamine turnover. Upregulated enkephalin in D1(-/-) mice is dependent on functional dopamine D3 receptors...

..In assuming that the well-recognised role of the D(1)-like family in regulating orofacial movements involves primarily D(1) receptors, a role for their D(5) counterparts may have been overlooked...

....

..They are regulated differentially by AC- and/or PLC-dependent processes and these processes involve distinct D1-like:D2-like interactions...

....

....