Decreased Thalamic Expression of the Homeobox Gene DLX1 in Psychosis

Kromkamp, Marjan; Uylings, H.B.M.; Smidt, Marten P.; Hellemons, Anita J. C. G. M.; Burbach, J. Peter H.; Kahn, René S.

doi:10.1001/archpsyc.60.9.869

Cited by 18 publications

(12 citation statements)

References 56 publications

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“…The glutamate data are noteworthy as they add to the increasing focus on this transmitter and its interaction with dopamine, [145][146][147][148][149][150][151] and will also be seen to be genetically pertinent. Third, concerning the timing of the synaptic pathology, there is altered expression in schizophrenia of several 'developmental' genes such as DLX1, 152 reelin, 153 and semaphorin 3A 154 , and correlations between their expression and that of other synaptic markers. 57,153 These findings provide some neuropathological support for a developmental basis to schizophrenia, perhaps via effects on synaptogenesis or synaptic pruning; however, they should not be overinterpreted, since every gene implicated in schizophrenia probably plays some role in brain development and, conversely, the very fact that so-called developmental genes continue to be expressed in adulthood implies that they have ongoing functions (which may or may not be the same as those during maturation).…”

Section: Synaptic Connectivity In Schizophreniamentioning

confidence: 99%

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

2004

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This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications. Molecular Psychiatry (2005) 10, 40-68.

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Section: Synaptic Connectivity In Schizophreniamentioning

confidence: 99%

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

2004

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“…MDGA1 is an adhesion molecule suggested to be important for radial migration along glial fibers [Takeuchi and O'leary, 2006], and RELN is a secreted extracellular matrix protein essential in the regulation of laminar positioning of cortical neurons, shown to act as both an attractant and stop signal for radially migrating neurons [Jossin, 2004], and play an important role in radial glial scaffold formation [Forster et al, 2002]. ITGA3 is involved in the termination of radial glial-guided migration induced by RELN [Dulabon et al, 2000], and DLX1 has been implicated in psychosis [Kromkamp et al, 2003]. Therefore, the findings of the present study support the hypothesis that abnormal neuronal migration is intrinsic to SZ pathology.…”

Section: Discussionmentioning

confidence: 99%

Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene

Kähler

Djurovic

Kulle

et al. 2008

American J of Med Genetics Pt B

106

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Several lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P < 0.05) in either a genotypic or allelic association test. All of these genes, except transcription factor DLX1, are involved in the adhesion between neurons and radial glial cells. Eight markers obtained nominal significance in both tests, and were located in intronic or 3'UTR regions of adhesion molecule MDGA1 and previously reported SZ candidate RELN. The most significant result was attained for MDGA1 SNP rs9462341 (unadjusted association results: genotypic P = 0.00095; allelic P = 0.010). Several haplotypes within MDGA1, RELN, ITGA3, and ENAH were nominally significant. Further studies in independent samples are needed, including upcoming genome wide association study results, but our data suggest that MDGA1 is a new SZ susceptibility gene, and that altered neuronal migration is involved in SZ pathology.

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“…Some of these genes and their expression products have been associated with psychotic symptoms, for example; DLX1 expression is decreased in the thalamus of individuals with psychosis compared with those without a history of psychosis and matched healthy controls (Kromkamp et al , 2003). Likewise, the homeogene Engrailed 2 which controls cerebellar development is associated with schizophrenia (Gourion et al , 2004).…”

Section: A Neurodevelopmental Dimension?mentioning

confidence: 99%

Toward a neurobiology of delusions

Corlett

Taylor

Wang³

et al. 2010

Progress in Neurobiology

347

380

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Delusions are the false and often incorrigible beliefs that can cause severe suffering in mental illness. We cannot yet explain them in terms of underlying neurobiological abnormalities. However, by drawing on recent advances in the biological, computational and psychological processes of reinforcement learning, memory, and perception it may be feasible to account for delusions in terms of cognition and brain function. The account focuses on a particular parameter, prediction error – the mismatch between expectation and experience – that provides a computational mechanism common to cortical hierarchies, frontostriatal circuits and the amygdala as well as parietal cortices. We suggest that delusions result from aberrations in how brain circuits specify hierarchical predictions, and how they compute and respond to prediction errors. Defects in these fundamental brain mechanisms can vitiate perception, memory, bodily agency and social learning such that individuals with delusions experience an internal and external world that healthy individuals would find difficult to comprehend. The present model attempts to provide a framework through which we can build a mechanistic and translational understanding of these puzzling symptoms.

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Decreased Thalamic Expression of the Homeobox Gene DLX1 in Psychosis

Abstract: Decreased thalamic expression of DLX1 in schizophrenia and bipolar disorder with psychosis suggests shared genetic deficits in expression of this homeobox gene.

Cited by 18 publications

References 56 publications

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene

Toward a neurobiology of delusions

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