ARIH1 deficiency impairs spatial learning and memory via GIRK2 upregulation in hippocampal CaMKII-expressing neurons in mice

Alterations of Ariadne RBR E3 Ubiquitin Protein Ligase 1 (ARIH1), a human homologue of Drosophila Ari, have been associated with a number of human diseases. Given the importance of ubiquitin-proteasome system in learning and memory, whether ARIH1 involves in the process has not been explored. Here we report that ARIH1-deficent mice exhibited a defect in learning and memory evidenced in Morris water maze and in novel object recognition tests without changes in basal motor activity, anxiety, and depressive behaviors. We found that ARIH1 deficiency resulted in an upregulation of G protein-gated inwardly rectifying potassium channel 2 (GIRK2) in dorsal hippocampus that was attributed to the impaired ubiquitination and degradation. Locally injection of ARIH1-expressing lentivirus to restore the ARIH1 expression of dorsal hippocampus in ARIH1 ^+/- mice restored the impaired learning and memory. Moreover, selective knockdown ARIH1 in dorsal hippocampal calcium-calmodulin-dependent protein kinase II (CaMKII)-expressing neurons, but not for parvalbumin ⁺ (PV) or somatostatin ⁺ (SST) neurons, in naïve mice was sufficient to mimic the damage in learning and memory of ARIH1 ^+/- mice. Lastly, we demonstrated that systemically or locally inhibition of GIRK activity was able to improve ARIH1 deficiency-induced decline of learning and memory in ARIH1 ^+/- mice. The present study discovered the clear role of ARIH1 in mediating learning and memory, defect of ARIH1 resulted in upregulation of GIRK2 in hippocampal CaMKII-expressing neurons via modulating the ubiquitination and degradation GIRK2.