Increased Interstitial White Matter Neuron Density in the Dorsolateral Prefrontal Cortex of People with Schizophrenia

Yang, Yang; Fung, Samantha J.; Rothwell, Alice; Si, Tianmei; Weickert, Cynthia Shannon

doi:10.1016/j.biopsych.2010.08.020

Cited by 101 publications

(134 citation statements)

References 56 publications

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“…However, the fact that thalamocortical tracts form early in development suggests that this abnormality could already be present at birth or in the first years of life and would be consistent with the neurodevelopmental nature of schizophrenia. Indeed, there is evidence for altered interstitial prefrontal neurons, considered remnants of the subplate (Kostovic et al, 2011), in schizophrenia (Akbarian et al, 1993;Anderson et al, 1996;Harrison, 2003, 2005;Kirkpatrick et al, 2003;Yang et al, 2011), supporting an early pathological process. Furthermore, as the PFC completes maturation well after the thalamocortical fibers have reached the subplate (Kostovic and Judas, 2010), it is conceivable that thalamic neuronal activity might be a potential effector of PFC maturation and developing function via its connectivity (Kanold, 2009).…”

Section: Discussionmentioning

confidence: 99%

Investigation of Anatomical Thalamo-Cortical Connectivity and fMRI Activation in Schizophrenia

Marenco

Stein

Savostyanova

et al. 2011

Neuropsychopharmacol

142

101

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The purpose of this study was to examine measures of anatomical connectivity between the thalamus and lateral prefrontal cortex (LPFC) in schizophrenia and to assess their functional implications. We measured thalamocortical connectivity with diffusion tensor imaging (DTI) and probabilistic tractography in 15 patients with schizophrenia and 22 age-and sex-matched controls. The relationship between thalamocortical connectivity and prefrontal cortical blood-oxygenation-level-dependent (BOLD) functional activity as well as behavioral performance during working memory was examined in a subsample of 9 patients and 18 controls. Compared with controls, schizophrenia patients showed reduced total connectivity of the thalamus to only one of six cortical regions, the LPFC. The size of the thalamic region with at least 25% of model fibers reaching the LPFC was also reduced in patients compared with controls. The total thalamocortical connectivity to the LPFC predicted working memory task performance and also correlated with LPFC BOLD activation. Notably, the correlation with BOLD activation was accentuated in patients as compared with controls in the ventral LPFC. These results suggest that thalamocortical connectivity to the LPFC is altered in schizophrenia with functional consequences on working memory processing in LPFC.

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Section: Discussionmentioning

confidence: 99%

Investigation of Anatomical Thalamo-Cortical Connectivity and fMRI Activation in Schizophrenia

Marenco

Stein

Savostyanova

et al. 2011

Neuropsychopharmacol

142

101

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“…Altered neuronal densities were reported in the prefrontal cortex (Akbarian et al, 1996;Anderson et al, 1996;Connor et al, 2009;Daviss and Lewis, 1995;Ikeda et al, 2004;Joshi et al, 2012;Morris et al, 2008;Rajkowska et al, 1998;Selemon et al, 1995Selemon et al, , 1998Selemon et al, , 2003Yang et al, 2011), auditory cortex (Dorph-Petersen et al, 2009), cingulate cortex (Benes, 1991(Benes, , 1993Brune et al, 2010;Connor et al, 2009), entorhinal cortex (Arnold et al, 1991;Falkai et al, 2000;Jakob and Beckmann, 1986;Kovalenko et al, 2003;Wang et al, 2011), fusiform cortex (Di Rosa et al, 2009), occipital cortex (Selemon et al, 1995), parietal cortex (Chance et al, 2005), visual cortex (Dorph-Petersen et al, 2007), thalamus (Young et al, 2000), hypothalamus (Bernstein et al, 1998), striatum (Kreczmanski et al, 2007), amygdala (Kreczmanski et al, 2007), and hippocampus (Konradi et al, 2011) in post-mortem brain tissue from schizophrenic patients. Interestingly, many of these reports show specific defects in GABAergic interneuron density or distribution (Benes et al, 1991;Chance et al, 2005;Daviss and Lewis, 1995;Di Rosa et al, 2009;Ikeda et al, 2004;Joshi et al, 2012;Konradi et al, 2011;Morris et al, 2008;Wang et al, 2011;Yang et al, 2011). While the majority of studies report decreased cell densiti...…”

Section: Anatomical and Histological Findings Suggest Neurodevelopmenmentioning

confidence: 99%

“…However, like the cell density studies, these data do not form a consensus. Some studies report increased density in the superficial white matter (Anderson et al, 1996;Connor et al, 2009;Eastwood and Harrison, 2005;Joshi et al, 2012;Kirkpatrick et al, 1999Kirkpatrick et al, , 2003Yang et al, 2011), whereas others report decreased density in superficial, but increased or variable density in deep white matter (Akbarian et al, 1993a(Akbarian et al, , b, 1996. Variation in patient populations, brain regions, or methodologies (such as particular molecular markers used to identify cells) may account for these discrepancies (Connor et al, 2009;Eastwood and Harrison, 2005;Harrison, 1999;Heckers, 1997;Meyer et al, 1992).…”

Section: Anatomical and Histological Findings Suggest Neurodevelopmenmentioning

confidence: 99%

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

Schmidt

Mirnics

2014

Neuropsychopharmacol

189

130

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The origins of schizophrenia have eluded clinicians and researchers since Kraepelin and Bleuler began documenting their findings. However, large clinical research efforts in recent decades have identified numerous genetic and environmental risk factors for schizophrenia. The combined data strongly support the neurodevelopmental hypothesis of schizophrenia and underscore the importance of the common converging effects of diverse insults. In this review, we discuss the evidence that genetic and environmental risk factors that predispose to schizophrenia disrupt the development and normal functioning of the GABAergic system.

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“…Films were developed using the AGFA CP1000 film developer (Agfa-Gevaert N.V., Mortsel, Belgium), scanned using a GS800 densitometer (BioRad, USA) and analysed using Multi-Analyst software (BioRad). Histological standards for quantitative analysis were previously defined by immunostaining (Yang et al, 2010). Experiments and quantification were performed blind to diagnosis.…”

Section: Human Tissue Dissection and Preparationmentioning

confidence: 99%

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

Matosin

Frank

Deng

et al. 2013

Schizophrenia Research

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Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [3H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia and 37 matched control subjects. Subsequently, we measured [3H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n = 6/group). Subjects with schizophrenia showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. Furthermore, mGluR5 binding in the rat cortex, thalamus, hippocampus and striatum was unaltered by short-, medium-and long-term antipsychotic treatment. Our data suggests that there are no alterations in mGluR5 in schizophrenia subjects. The lack of alteration in mGluR5 binding and protein in schizophrenia is advantageous because its ability to modulate the NMDAR is potentially unhindered, thereby supporting the development of novel antipsychotic agents that work through the mGluR5/NMDAR complex. ', Schizophrenia Research, vol. 146,[1][2][3] AbstractMetabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [ 3 H]MPEP binding to mGluR5 and mGluR5 protein density in post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia subjects (including 7 schizoaffective) and 37 matched controls. Subsequently, we measured [ 3 H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n=6/group). Subjects with schizophrenia (n=30) showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. However subjects with schizoaffective disorder (n=7) displayed a trend towards reduced mGluR5 binding (20%) compared to schizophrenia subjects (p=0.079), suggesting different underlying biochemistry of the disorder. In schizoaffective subjects of depressive subtype (n=4), mGluR5 binding was reduced by 39% compared to controls (p=0.022). Furthermore, mGluR5 binding in the rat cortex, thalamus, hippocampus and striatum was unaltered by short-, medium-and long-term antipsychotic treatment. Our data suggests that there are diagnostic specific alte...

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Increased Interstitial White Matter Neuron Density in the Dorsolateral Prefrontal Cortex of People with Schizophrenia

Cited by 101 publications

References 56 publications

Investigation of Anatomical Thalamo-Cortical Connectivity and fMRI Activation in Schizophrenia

Investigation of Anatomical Thalamo-Cortical Connectivity and fMRI Activation in Schizophrenia

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

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