WNT Signaling Influences Neurological Function and Psychiatric Disorders Through Regulating Glia Phenotypes and Neuron Plasticity

Abstract Background: As an important signaling pathway during embryonic development, WNT/β-catenin signaling regulates cell proliferation and differentiation. However, the role of WNT pathway on central nervous system (CNS) injury is not clear. Methods: In this study, based on traumatic brain injury (TBI, in vivo) and acute neuroinflammation (in vivo and in vitro) models, WNT signaling regulating glia cell phenotypes and the fate of neurons was investigated, and the effect on neurological function and anxiety behavior were also studied. The intercellular interaction was verified by transwell experiments. Results: The result showed that WNT signaling was inhibited at acute stage of brain injury and TBI, and the expression of WNT/β-catenin decreased in primary cultured neurons and astrocytes after lipopolysaccharide (LPS) treatment. WNT agonists (LiCl and Wnt3a) treatment significantly relieved psychiatric symptoms post-TBI compared to vehicle-treated group. WNT agonist treatment accelerated the polarization of astrocytes and generated A2 astrocytes, and activation of WNT signaling in astrocytes could promote neuron axon formation and maintain neuronal stability. Conclusions: Our findings revealed that WNT signaling could influence neuron plasticity through regulating the phenotypes of microglia and astrocytes, and thereby affect neurological function and anxiety state. This study provides an evidence that WNT signaling may be therapeutic target against psychiatric disorder after TBI