Mutant disrupted‐in‐schizophrenia 1 in astrocytes: Focus on glutamate metabolism

Abazyan, Sofya; Yang, Eun Ju; Abazyan, Bagrat; Meng, Xin; Yang, Chunxia; Rojas, Camilo; Slusher, Barbara S.; Sattler, Rita; Pletnikov, Mikhail V.

doi:10.1002/jnr.23459

Cited by 16 publications

(13 citation statements)

References 52 publications

(69 reference statements)

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“…1 and Table 1). As mutant DISC1 decreases D-serine production by astrocytes (Ma et al 2013;Abazyan et al 2014), we evaluated whether adding D-serine to cultured neurons would ameliorate deficient dendritic arborization. D-serine treatment significantly restored reduced dendritic length, cell volume, cell area, and had borderline effects on number of dendritic branches and segments in neurons co-cultured with mutant DISC1 astrocytes.…”

Section: Resultsmentioning

confidence: 99%

DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders

Meng

Zhu

Shevëlkin

et al. 2016

Journal of Neurochemistry

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Disrupted-In-Schizophrenia 1 (DISC1) is a genetic risk factor implicated in major mental disorders that involve disrupted neurodevelopment and synaptic signaling. Glial cells such as astrocytes can regulate neuronal and synaptic maturation. Although astrocytes express DISC1, the role of astrocyte DISC1 in synaptic regulation remains unknown. We expressed a pathogenic, dominant-negative form of DISC1, mutant DISC1, in astrocytes to elucidate the roles of astrocytic DISC1 in maturation of dendrites and excitatory and inhibitory synapses using a co-culture model. We found that wild-type primary neurons exhibited less elaborated dendritic arborization when co-cultured with astrocytes that express mutant DISC1, compared to control astrocytes. We observed significantly decreased density of excitatory but not inhibitory synapses on wild-type primary neurons that were co-cultured with astrocytes that express mutant DISC1, compared to control astrocytes. Treatment of co-cultures with D-serine restored dendritic development and density of excitatory synapses. Our findings show for the first time that mutant DISC1 diminished the capacity of astrocytes to support dendritic and synaptic maturation in co-cultured neurons, and that D-serine can restore the dendritic and synaptic abnormalities. The results provide a new insight into the mechanisms whereby genetic risk factors within astrocytes could contribute the pathogenesis of psychiatric disorders.

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Section: Resultsmentioning

confidence: 99%

DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders

Meng

Zhu

Shevëlkin

et al. 2016

Journal of Neurochemistry

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“…Furthermore, genetic variants of DISC1 were shown to be associated with the hippocampal volume [28], cortical thickness [29], and prefrontal-associated cognition [25]. DISC1 protein is predominantly localized in neurons ( [30] and many others), but there is also evidence for a wide extra-neuronal expression (i.e., in cultured astrocytes, OLs, microglia, and radial progenitor cells, [1,23,[31][32][33]). The recently discovered abundant expression of DISC1 in human and rodent OLs [1,23,[33][34][35], together with the well-established influence of DISC1 on white matter integrity [36][37][38], raises the issue, whether OL-associated DISC1 might be part of the aforementioned profound white matter abnormalities in schizophrenia.…”

Section: Introductionmentioning

confidence: 98%

Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid schizophrenia

Bernstein

Jauch

Dobrowolny

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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Profound white matter abnormalities have repeatedly been described in schizophrenia, which involve the altered expression of numerous oligodendrocyte-associated genes. Transcripts of the disrupted-in-schizophrenia 1 (DISC1) gene, a key susceptibility factor in schizophrenia, have recently been shown to be expressed by oligodendroglial cells and to negatively regulate oligodendrocyte differentiation and maturation. To learn more about the putative role(s) of oligodendroglia-associated DISC1 in schizophrenia, we analyzed the density of DISC1-immunoreactive oligodendrocytes in the fronto-parietal white matter in postmortem brains of patients with schizophrenia. Compared with controls (N = 12) and cases with undifferentiated/residual schizophrenia (N = 6), there was a significantly increased density of DISC1-expressing glial cells in paranoid schizophrenia (N = 12), which unlikely resulted from neuroleptic treatment. Pathophysiologically, over-expression of DISC1 protein(s) in white matter oligodendrocytes might add to the reduced levels of two myelin markers, 2',3'-cyclic-nucleotide 3'-phosphodiesterase and myelin basic protein in schizophrenia. Moreover, it might significantly contribute to cell cycle abnormalities as well as to deficits in oligodendroglial cell differentiation and maturation found in schizophrenia.

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“…We found that expression of C terminus-truncated DISC1 (mutant DISC1), a putative product of chromosomal translocation in a Scottish pedigree [7], disrupts this binding property in a dominant-negative manner, resulting in increased degradation of serine racemase via ubiquitination and decreased production of D -serine [5]. Notably, these changes were observed in astrocytes but not in neurons that expressed mutant DISC1 [5,8], suggesting that mutant DISC1 may exert cell type-specific effects.…”

Section: Introductionmentioning

confidence: 99%

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

et al. 2016

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Despite the recent progress in psychiatric genetics, very few studies have focused on genetic risk factors in glial cells that, compared to neurons, can manifest different molecular pathologies underlying psychiatric disorders. In order to address this issue, we studied the effects of mutant disrupted in schizophrenia 1 (DISC1), a genetic risk factor for schizophrenia, in cultured primary neurons and astrocytes using an unbiased mass spectrometry-based proteomic approach. We found that selective expression of mutant DISC1 in neurons affects a wide variety of proteins predominantly involved in neuronal development (e.g., SOX1) and vesicular transport (Rab proteins), whereas selective expression of mutant DISC1 in astrocytes produces changes in the levels of mitochondrial (GDPM), nuclear (TMM43) and cell adhesion (ECM2) proteins. The present study demonstrates that DISC1 variants can perturb distinct molecular pathways in a cell type-specific fashion to contribute to psychiatric disorders through heterogenic effects in diverse brain cells.

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Mutant disrupted‐in‐schizophrenia 1 in astrocytes: Focus on glutamate metabolism

Cited by 16 publications

References 52 publications

DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders

DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders

Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid schizophrenia

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

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