Expression Of P2Y₁₃ In Oligodendrocytes And Its Role In Demyelinating Diseases

Oligodendrocytes are the myelin-forming cells for axon ensheathment in the central nervous system,which is important for maintaining the conduction velocity of nerve impulses.Oligodendrocyte,providing nutrition for the axons,plays an important role in maintaining the integrity of axons,energy metabolism,and regulating neuronal survival through neurotrophic factors.Many diseases of the central nervous system such as multiple sclerosis,white matter malnutrition,cerebral spinal cord injury,senile dementia,schizophrenia,amyotrophic lateral sclerosis,are closely related to oligodendrocyte dysplasia,accompanied by demyelination.In the pathological conditions such as nervous system damage,oligodendrocytes are very prone to death due to the metabolic characteristics and the extreme sensitivity to various adverse factors,leading to demyelination.In the CNS,neuronal activity influences myelination by activating purinergic signalling.Myelination is regulated by extracellular signals and intracellular factors,which effect on both oligodendrocyte maturation and axonal activity.It has been pointed out that ATP and ADP can inhibit OPC proliferation in purified primary cell culture model and cerebellar tissue sections.In addition to UTP,ATP and ADP are more effective in stimulating OPC migration and promoting oligodendrocyte differentiation than PDGF.Recently,purinergic signalling has been found to stimulate myelination at later developmental stage of oligodendrocyte.A large number of studies have shown that a variety of P2 Y receptors have been involved in the development of oligodendrocytes.Based on the above facts,we further investigated the role of purinergic receptor P2Y₁₃ in myelination of mouse.We used immunofluorescence and in situ hybridization to detect the expression of P2Y₁₃ receptor.It is showed that the P2Y₁₃ receptor was expressed in different developmental stages?P1,P10,P20,P40?,which increased first and then decreased.And P2Y₁₃ receptors are specifically expressed in oligodendrocytes,especially in pre-oligodendrocyte and in the early stage of mature-oligodendrocyte.In vitro purified culture system,P2Y₁₃ stimulation can enhance OPC differentiation by increasing myelin basic protein?MBP?expression while P2Y₁₃ inhibition can decrease MBP expression.In the cuprizone model,the expression of MBP in the corpus callosum decreased first and then increased.Then,P2Y₁₃ specific agonist SC251675 enhance remyelination while P2Y₁₃ specific antagonist MRS2211 delay remyelination in the cuprizone model examined by Western blot and qPCR.This effect appears to result from inhibiting the differentiation of OPCs as more NG2+ OPCs but less MBP+ oligodendrocytes were observed in the P2Y₁₃ KO mice.We performed behavior experiments on P2Y₁₃ KO mice and WT mice.In the elevated plus maze test,P2Y₁₃ KO mice had a significant decrease in the number of open arms,the percentage of open arm retention time and total entries,which indicated that P2Y₁₃ KO mice are more anxious than wild-type mice.In the forced swim test and the morris water maze test,there is no difference between P2Y₁₃ KO mice and WT mice.This study has the following highlights:?1?P2Y₁₃ is specifically expressed in pre-oligodendrocyte and in the early stage of mature-oligodendrocyte;?2?P2Y₁₃ can regulate oligodendrocyte differentiation and promote remyelination in cuprizone model;?3?Behavioral studies have shown that P2Y₁₃ KO mice are more anxious than wild-type mice.This provides a new idea for demyelinating disease and provides new therapeutic strategies for clinical treatment.