Abstract
Adolescence is the critical time for developing proper oligodendrocyte (OL)-neuron interaction and the peak of onset for many cognitive diseases, among which anxiety disorders display the highest prevalence. However, whether impairment of de novo OL development causes neuronal abnormalities and contributes to the early onset of anxiety phenotype in childhood still remains unexplored. In this study, we tested the hypothesis that defects in OL maturation manifests cortical neuron function and leads to anxiety-like behaviors in juvenile mice. We report here that conditional knockout of the Olig2 gene (Olig2 cKO) specifically in differentiating OLs in the mouse brain preferentially impaired OL maturation in the gray matter of cerebral cortex. Interestingly, localized proton magnetic resonance spectroscopy revealed that Olig2 cKO mice displayed abnormally elevated cortical glutamate levels. In addition, transmission electron microscopy demonstrated increased vesicle density in excitatory glutamatergic synapses in the cortex of the Olig2 cKO mice. Moreover, juvenile Olig2 cKO mice exhibited anxiety-like behaviors and impairment in behavioral inhibition. Taken together, our results suggest that impaired OL development affects glutamatergic neuron function in the cortex and causes anxiety-related behaviors in juvenile mice. These discoveries raise an intriguing possibility that OL defects may be a contributing mechanism for the onset of anxiety in childhood.
Highlights
Adolescence is a peak time for the onset of numerous mental disorders, represented by anxiety, impulse control disorders, and schizophrenia (Paus et al, 2008)
To investigate the effects of Olig2 loss on OL development, we quantified oligodendroglia progenitor cells (OPCs) marked by immunohistochemistry staining of PDGF receptor α (PDGFRα) and mature OL marked by CC1
To explore whether and how impaired OL maturation may interfere with neuronal function in the juvenile brain, we examined the spectrum of neurochemicals in the cortex of WT and Olig2 cKO mice at the age of postnatal day 21 (P21) using proton magnetic resonance spectroscopy (1H MRS)
Summary
Adolescence is a peak time for the onset of numerous mental disorders, represented by anxiety, impulse control disorders, and schizophrenia (Paus et al, 2008). Molecular and cellular mechanisms that lead to anxiety in adolescence remain unknown, which is a prevailing issue in understanding the early onset of mental dysfunction. Recent clinical studies revealed that aberrantly elevated glutamate levels in the anterior cingulate cortex were positively correlated with clinical symptoms of anxiety and impulsivity in patients (Phan et al, 2005; Hoerst et al, 2010; Modi et al, 2014). These findings suggest that abnormal cortical glutamate homeostasis may contribute to the pathogenesis of anxiety disorders, while the underlying mechanisms remain undefined
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