Roles of prokineticin 2 in electroconvulsive shock-induced memory impairment via regulation of phenotype polarization in astrocytes.

ABSTRACT

Electroconvulsive shock (ECT) is the most effective treatment for depression but can impair learning and memory. ECT is increasingly being shown to activate astrocytes and induce neuroinflammation, resulting in cognitive decline. Activated astrocytes can differentiate into two subtypes, A1-type astrocytes and A2-type astrocytes. Regarding cognitive function, neurotoxic A1 astrocytes and neuroprotective A2 astrocytes may exhibit opposite effects. Specifically, prokineticin 2 (PK2) functions as an essential mediator of inflammation and induces a selective A2-protective phenotype in astrocytes. This study aimed to clarify how PK2 promotes improved learning memory following electroconvulsive shock (ECS). As part of the study, rats were modeled using chronic unpredictable mild stress. Behavioral experiments were conducted to assess their cognitive abilities and depression-like behaviors. Western blot was used to determine the expression of PK2. Immunohistochemical and electron microscopy analyses of the hippocampal CA1 region were conducted to study the activation of astrocyte subtypes and synaptic ultrastructure, respectively. In this study, rats' spatial learning and memory impairment began to improve as activated A1-subtype astrocytes gradually decreased, and PK2 and A2 phenotype activation peaked on the third day after ECS. PKRA7 (PK2 antagonist) inhibits A2-type astrocyte activation partially and suppresses spatial learning and memory improvement. Collectively, our findings support that PK2 may induce a selective modulation of astrocytic polarization to a protective phenotype to promote learning and memory improvement after ECS.