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.

Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells

“…; Xia et al . ). In contrast, the physiological and pathological roles of SR/ d ‐serine in the retina are relatively scant, but SR/ d ‐serine has been implicated in diabetic retinopathy (Jiang et al .…”

Astrocytic Regulation of Glutamate Transmission in Schizophrenia

“…Selective expression of mutant DISC1 in astrocytes decreased protein levels of SR by increasing its ubiquitination ( 88 ). Astrocytes expressing mutant DISC1 caused less elaborated dendritic arborization and decreased the density of excitatory synapses in co-cultured normal neurons ( 89 ). The downregulation of SR resulted in a significant decline in D-serine levels, an enhanced locomotor activity, and impaired responses to pre-pulse inhibition in the mutant mice ( 88 ).…”

Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position 84 as a hot spot for β-elimination function

“…On the other hand, low D-serine levels (i.e. SR hypofunction) have been correlated with schizophrenia (21)(22)(23). In contrast to these examples of SR dysregulation, in the healthy brain, basal D-serine signaling is essential for synaptic efficiency and long-term potentiation associated with learning and memory (24).…”