title: DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders.
abstract: 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. Expression of mutant DISC1 (mDISC1) in astrocytes (A) decreases binding of endogenous DISC1 to serine racemase (SR) and production of D-serine (blue triangles) from L-serine (red triangles). As a result, neurons co-cultured with mutant DISC1 astrocytes exhibit diminished dendritic arborization (DIV10) and decreased linear density of VGLUT+(red)/PSD95 +  (green) excitatory synapses (DIV14). Filled circles with arrows denote membrane transporters for D-serine. Read the Editorial Highlight for this article on doi: 10.1111/jnc.13699.
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Preclinical College, Guangxi University of Chinese Medicine, Nanning, Guangxi Province, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Shevelkin
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Departments of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Departments of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pletnikov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D001523:Mental Disorders / Q000378:metabolism*; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000378:metabolism; D018408:Patch-Clamp Techniques; D013569:Synapses / Q000378:metabolism*
chemical_list: C498794:Disc1 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins
keywords: D-serine; GABA receptors; glutamate receptors; neuron-astrocyte co-culture; psychiatric disease