Reduced Oligodendrocyte Precursor Cell Impairs Astrocytic Development in Early Life Stress

Abstract

Astrocyte maldevelopment is implicated in various neuropsychiatric diseases associated with early life stress. However, the underlying astrocytopathy mechanism, which can result in the psychiatric symptoms, remains unclear. In this study, it is shown that a reduced oligodendrocyte precursor cell (OPC) population accompanies hindered hippocampal astrocytic development in an improved parental isolation mouse model, and that the loss of OPCs suppresses astrocytic network formation and activity. It is further demonstrated that OPC‐derived Wnt ligands, in particular Wnt7b, are required for Wnt/β‐catenin pathway‐mediated astrocytic development and subsequent effects related to neuronal function. In addition, focal replenishment of Wnt7a/b is sufficient to rescue astrocytic maldevelopment. These results elucidate a Wnt‐paracrine‐dependent but myelin‐independent role of OPCs in regulating astrocytic development, which provides a unique insight into the astrocytopathy mechanism in early life stress, and can be implicated in the pathogenesis of human early life stress‐related neuropsychiatric disorders.

Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model

“…Our study further corroborates the multi-functional role of OPCs in the central nervous system (CNS). In other neurological disorders, such as multiple sclerosis, hypoxic-ischemic encephalopathy, and psychiatric diseases, OPCs not only contribute to aberrant myelin formation [ 39 , 57 ], but are also involved in the regulation of blood-brain barrier integrity [ 42 ], CNS immune regulation [ 59 , 60 ] and the behavioral outcomes [ 61 , 62 ]. In the present study, we provided new evidence that selective enhancement of DISC1 exon 3 splicing in OPCs, disrupts the formation of vGLUT1 + excitatory synapse but not vGAT + inhibitory synapse.…”

Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model

“…Our study further corroborates the multi-functional role of OPCs in the central nervous system (CNS). In other neurological disorders, such as multiple sclerosis, hypoxic-ischemic encephalopathy, and psychiatric diseases, OPCs not only contribute to aberrant myelin formation 33,51 , but are also involved in the regulation of blood-brain barrier integrity 36 , CNS immune regulation 53,54 and the behavioral outcomes 55,56 . In the present study, we generated a novel transgenic mouse strain to model the heterozygous DISC1 exon 3 splicing in patients with schizophrenia, and provided new evidence that such manipulation of DISC1 gene transcription exclusively in OPCs causes OPC hypertrophy, disrupts the formation of vGLUT1 + excitatory synapses, and initiate schizophrenia-like symptoms.…”

Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes

“…In a parental isolation mouse model, NG2-glia mediate the development of astrocytes in the hippocampus through the Wnt/β-catenin signaling pathway. The loss of NG2-glia inhibits the development and function of astrocytes [ 104 ]. In contrast to other glia and neurons, high-glucose exposure does not cause oxidative stress in NG2-glia cultures [ 65 ].…”