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DISC 1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders
Author(s) -
Xia Meng,
Zhu Shanshan,
Shevelkin Alexey,
Ross Christopher A.,
Pletnikov Mikhail
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13663
Subject(s) - disc1 , excitatory postsynaptic potential , astrocyte , neuroscience , inhibitory postsynaptic potential , biology , microbiology and biotechnology , mutant , synapse , central nervous system , biochemistry , gene
Disrupted‐In‐Schizophrenia 1 ( DISC 1) 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 DISC 1, the role of astrocyte DISC 1 in synaptic regulation remains unknown. We expressed a pathogenic, dominant‐negative form of DISC 1, mutant DISC 1, in astrocytes to elucidate the roles of astrocytic DISC 1 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 DISC 1, 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 DISC 1, 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 DISC 1 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 DISC 1 ( mDISC 1) in astrocytes (A) decreases binding of endogenous DISC 1 to serine racemase ( SR ) and production of D‐serine (blue triangles) from L‐serine (red triangles). As a result, neurons co‐cultured with mutant DISC 1 astrocytes exhibit diminished dendritic arborization ( DIV 10) and decreased linear density of VGLUT +(red)/ PSD 95 + (green) excitatory synapses ( DIV 14). Filled circles with arrows denote membrane transporters for D‐serine. Read the Editorial Highlight for this article on doi: 10.1111/jnc.13699 .