Microglial activation in the dorsal striatum participates in anxiety-like behavior in Cyld knockout mice

CYLD lysine 63 deubiquitinase (CYLD), that is mainly involved in immune responses and inflammation, is expressed at high levels in the brain, especially in the dorsal striatum, but its physiological function of CYLD in the brain remains unexplored. The present study investigated the effect of Cyld gene knockout on behavior relevant to the dorsal striatum, such as motor activity and depression-like and anxiety-like behavior. Microglia and the pro-inflammatory cytokines including interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha were evaluated in the dorsal striatum to elucidate the underlying mechanism. Cyld knockout (Cyld(-/-)) mice exhibited anxiety-like behavior, but not motor deficits or depression-like behavior. Microglia were activated and the mRNA levels of IL1 beta and TNF-alpha were increased in the dorsal striatum of Cyld(-/-) mice compared to Cyld(+/+) mice. The microglial modulator minocycline partially reversed the anxiety-like behavior, microglial activation and increase in IL-1 beta and TNF-alpha mRNA and protein levels in the dorsal striatum of Cyld(-/-) mice. Collectively, these results suggest that Cyld knockout leading to microglial activation promotes IL-1 beta and TNF-alpha expression and acts as a critical pathway in the pathophysiology of anxiety.