Heat shock protein A12A (HSPA12A) is a novel member of multigene HSP70 family. This study investigated whether HSPA12A plays a role in the development of affective behaviors and adult hippocampal neurogenesis in mice.

HSPA12A (Hspa12a^-/-) mice were generated by Cre-LoxP recombinant system. Mice affective behaviors were tested by sucrose preference, open field, elevated plus maze, forced swim, tail suspension and self-grooming. Neurogenesis was examined by BrdU-labeling and immunofluorescence staining. Spinogenesis was examined by Golgi staining. Molecular signaling was evaluated by Immunoblotting analysis.

HSPA12A expression was upregulated in hippocampus but not in cortex in response to acute restraint swimming stress, while deficiency of HSPA12A in mice resulted in aberrant behaviors including anhedonia, increased anxiety and reduced depression. We also found an impaired spinogenesis and neurogenesis in the hippocampal dentate gyrus of Hspa12a^-/- mice. Moreover, Hippocampus of Hspa12a^-/- mice showed decreased phosphorylation levels of GSK-3 and ERKs whereas increased phosphorylation level of b-Catenin, respectively, compared to the wild type littermate controls. A downregulated expression of BDNF was also observed in Hippocampus of Hspa12a^-/- mice. Notably, administration with lithium, a chemical frequently used for GSK-3 inhibition, ameliorated the HSPA12A deficiency-induced aberrant affective behaviors and impaired neurogenesis.