Prothymosin alpha-deficiency enhances anxiety-like behaviors and impairs learning/memory functions and neurogenesis

Prothymosin alpha (ProT alpha) is expressed in various mammalian organs including the neuronal nuclei in the brain, and is involved in multiple functions, such as chromatin remodeling, transcriptional regulation, cell proliferation, and survival. ProT alpha has beneficial actions against ischemia-induced necrosis and apoptosis in the brain and retina. However, characterizing the physiological roles of endogenous ProT alpha in the brain without stress remains elusive. Here, we generated ProT alpha-deficiency mice to explore whether endogenous ProT alpha is involved in normal brain functions. We successfully generated heterozygous ProT alpha knockout (ProT alpha(+/-)) mice, while all homozygous ProT alpha knockout (ProT alpha(-/-)) offspring died at early embryonic stage, suggesting that ProT has crucial roles in embryonic development. In the evaluation of different behavioral tests, ProT alpha(+/-) mice exhibited hypolocomotor activity in the open-field test and enhanced anxiety-like behaviors in the light/dark transition test and the novelty induced hypophagia test. ProT alpha(+/-) mice also showed impaired learning and memory in the step-through passive avoidance test and the KUROBOX test. Depression-like behaviors in ProT alpha(+/-) mice in the forced swim and tail suspension tests were comparable with that of wild-type mice. Furthermore, adult hippocampal neurogenesis was significantly decreased in ProT alpha(+/-) mice. ProT alpha(+/-) mice showed an impaired long-term potentiation induction in the evaluation of electrophysiological recordings from acute hippocampal slices. Microarray analysis revealed that the candidate genes related to anxiety, learning/memory-functions, and neurogenesis were down-regulated in ProT alpha(+/-) mice. Thus, this study suggests that ProT has crucial physiological roles in the robustness of brain.