The Involvement of the Decrease of Astrocytic Wnt5a in the Cognitive Decline in Minimal Hepatic Encephalopathy

Wnt signaling plays a key role in neuroprotection and synaptic plasticity. We speculate that the impairment of Wnt signaling may mediate astrocytic neurotrophins (NTs) production and the impairment of Wnt signaling to astrocytic NTs production contributes to the pathogenesis of minimal hepatic encephalopathy (MHE). Here, we found that induction of astrocytic NTs synthesis was by Wnt5a via the calcium/calmodulin-sensitive protein kinase II (CaMK II)-cAMP-response element-binding protein (CREB) pathway in PCAs. The decrease of spatial learning and memory and downregulation of astrocytic BDNF and NT-3 were reversed by Wnt5a in MHE rat model. The increased association between CaMK II and CREB followed by phosphorylation of CREB in response to Wnt5a stimulation was suppressed in the MHE rat model. Our results highlight a novel pathogenesis of the contribution of downregulation of NTs to the inhibition of the interaction between Wnt5a and Frizzled-2 in astrocytes in MHE.