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Patients with neuropathic pain often experience comorbid psychiatric disorders. Cellular plasticity in the anterior cingulate cortex (ACC) is assumed as a critical interface for pain perception and emotion. However, substantial efforts thus far are focused on intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes.Laminin is a key element of extracellular matrix (ECM) consisting of one -, and -chain and implicated in several pathophysiological processes. Here we showed that Laminin 1 (LAMB1) in ACC is significantly downregulated upon peripheral neuropathy. Knocking down ACC LAMB1 exacerbated pain sensitivity and induced anxiety and depression. Mechanistic analysis revealed that loss of LAMB1 causes actin dysregulation via interaction with integrin 1 and subsequent Src-dependent RhoA/LIMK/cofilin pathway, leading to increased presynaptic transmitter release probability and abnormal postsynaptic spine remodeling, which in turn orchestrates structural and functional plasticity of pyramidal neurons and eventually results in pain hypersensitivity and anxiodepression. This study shed new light on the functional capability of ECM, LAMB1 in modulating pain plasticity and revealed a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified cingulate LAMB1/integrin 1 as a promising therapeutic strategy for treatment of neuropathic pain and associated anxiodepression.

Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and 5-hydroxymethylcytosine (5hmC) profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2, impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice.

No abstract

DNA methylation is critical for oligodendrocyte development. The role of the converse process, DNA demethylation regulated by Ten-Eleven-Translocation (TET) dioxygenases, in oligodendrocyte homeostasis, myelination and remyelination however remains elusive. Here, we identify a genomewide and locus-specific DNA hydroxymethylation landscape shift during oligodendrocyte progenitor cell (OPC) differentiation. Tet1 ablation results in defects in oligodendrocyte development and myelination in the developing brain, while impairing remyelination after demyelination in adult brains.Transcriptomic and DNA hydroxymethylation analyses reveal a TET1-regulated epigenetic program for oligodendrocyte differentiation and identify a set of target genes associated with Ca 2+ homeostasis. Tet1-deficient OPCs exhibited reduced [Ca 2+ ] oscillations, while activation of calcium channels partially restores the differentiation defect of Tet1-deficient OPCs. Moreover, dysregulated oligodendrocyte homeostasis caused by Tet1-deficiency impairs action potential propagation and synaptic transmission. Thus, our results suggest that stage-specific TET1-mediated epigenetic programming of oligodendrocyte homeostasis is required for proper myelination and repair as well as neuronal physiology in cell-autonomous and non-cell-autonomous mechanisms, respectively.