BKM120 alters the migration of doublecortin-positive cells in the dentate gyrus of mice.

ABSTRACT

BKM120 is an inhibitor of class I phosphoinositide 3-kinases and its anti-cancer effects have been demonstrated in various solid cancer models. BKM120 is highly brain permeable and has been reported to induce mood disturbances in clinical trials. Therefore, we examined whether BKM120 produces anxiety- and depression-like behaviors in mice, as with patients receiving BKM120 in clinical trials. In this study, repeated BKM120 treatment (2.0 or 5.0 mg/kg, i.p., five times at 12-h interval) significantly induced anxiety- and depression-like behaviors in mice. Although abnormal changes in hippocampal neurogenesis have been suggested to, at least in part, associated with the pathogenesis of depression and anxiety, BKM120 did not affect the incorporation of 5-bromo-2'-deoxyuridine or the expression of doublecortin (DCX); however, it significantly enhanced the radial migration of DCX-positive cells in the dentate gyrus. BKM120-induced changes in migration were not accompanied by obvious neuronal damage in the hippocampus. Importantly, BKM120-induced anxiety- and depression-like behaviors were positively correlated with the extent of DCX-positive cell migration. Concomitantly, p-Akt expression was significantly decreased in the dentate gyrus. Moreover, the expression of p-c-Jun N-terminal kinase (JNK), p-DCX, and Ras homolog family member A (RhoA)-GTP decreased significantly, particularly in aberrantly migrated DCX-positive cells. Together, the results suggest that repeated BKM120 treatment enhances the radial migration of DCX-positive cells and induces anxiety- and depression-like behaviors by regulating the activity of Akt, JNK, DCX, and RhoA in the dentate gyrus. It also suggests that the altered migration of adult-born neurons in the dentate gyrus plays a role in mood disturbances.