ITPR2 Mediated Calcium Homeostasis in Oligodendrocytes is Essential for Myelination and Involved in Depressive‐Like Behavior in Adolescent Mice

Abstract

Ca2+ signaling is essential for oligodendrocyte (OL) development and myelin formation. Inositol 1,4,5‐trisphosphate receptor type 2 (ITPR2) is an endoplasmic reticulum calcium channel and shows stage‐dependent high levels in postmitotic oligodendrocyte precursor cells (OPCs). The role and potential mechanism of ITPR2 in OLs remain unclear. In this study, it is revealed that loss of Itpr2 in OLs disturbs Ca2+ homeostasis and inhibits myelination in adolescent mice. Animals with OL‐specific deletion of Itpr2 exhibit anxiety/depressive‐like behaviors and manifest with interrupted OPC proliferation, leading to fewer mature OLs in the brain. Detailed transcriptome profiling and signal pathway analysis suggest that MAPK/ERK‐CDK6/cyclin D1 axis underlies the interfered cell cycle progression in Itpr2 ablated OPCs. Besides, blocking MAPK/ERK pathway significantly improves the delayed OPC differentiation and myelination in Itpr2 mutant. Notably, the resting [Ca2+]i is increased in Itpr2 ablated OPCs, with the elevation of several plasma calcium channels. Antagonists against these plasma calcium channels can normalize the resting [Ca2+]i level and enhance lineage progression in Itpr2‐ablated OPCs. Together, the findings reveal novel insights for calcium homeostasis in manipulating developmental transition from OPCs to pre‐OLs; additionally, the involvement of OLs‐originated ITPR2 in depressive behaviors provides new therapeutic strategies to alleviate myelin‐associated psychiatric disorders.

Interaction between Oligodendrocytes and Interneurons in Brain Development and Related Neuropsychiatric Disorders

“…Moreover, the anti-depressant venlafaxine, a serotonin-and norepinephrine-reuptake inhibitor, successfully improved cognitive impairment and depression-like behaviors in a cuprizone-induced demyelinated mouse model [68]. In our recent research, we revealed novel insights for calcium homeostasis in manipulating developmental transition from OPCs to pre-OLs [69]. We also showed that the loss of the endoplasmic reticulum calcium channel ITPR2 in OLs induces anxiety-/depressive-like behaviors in the mice.…”

“…Dysmyelination during adolescent PFC development in mice model [55,57,58,61] Decreased expression of GAD67 in PV+ interneurons of SCZ patients [62] Conditional knockout of Gababr in OPCs interrupting the impaired bidirectional OPC-interneuron signaling and induing defective social cognitive behavior in the mice [52] Impaired electroencephalogram synchronization in the gamma range, originated mainly from PV+ interneurons, in SCZ patients [59] Fewer inhibitory synapses from interneurons onto cortical pyramidal cells in SCZ individuals [63] Defects in potent excitatory drives from pyramidal cells, causing the failure in recruiting PV + interneurons in mice models [65] Impaired excitation of interneurons in both mouse models and SCZ patients [65] Decreased excitatory drive to PV + interneurons, leading to a reduced expression of GAD67 mRNA [66] Depression Decreased myelin gene expression and impaired myelin formation in protracted social-isolation mice [66] Myelin genes are the most significantly downregulated in stress-induced depressive mice [67] Cuprizone-induced demyelinating mice develop depression-like behaviors [68] Calcium homeostasis in OLs is essential for myelination and causes anxiety/depressive like behaviors once interrupted in OLs [69] Animal models of chronic unpredictable mild stress show a decreased expression of OL-associated genes [70] Myelin gene mutation might be a causative of catatonia-depression syndrome in patients [71] Interneurons exhibit abnormal morphology and function in sMDD patients [72] Targeting the 5-HT2C receptor can restore neuronal activity deficits in sMDD GABAergic interneurons [72]…”