Effects of mood stabilizers on adult dentate gyrus-derived neural precursor cells

Abstract

Neurogenesis in the adult dentate gyrus (DG) is considered to be partly involved in the action of mood stabilizers. However, it remains unclear how mood stabilizers affect neural precursor cells in adult DG. We have established a culture system of adult rat DG-derived neural precursor cells (ADP) and have shown that lithium, a mood stabilizer, and dexamethasone, an agonist of glucocorticoid receptor, reciprocally regulate ADP proliferation. Neurogenesis constitutes not only proliferation of neural precursor cells but also apoptosis and differentiation. To develop further understanding of mood stabilizer effects on neural precursor cells in adult DG, we investigated and compared the effects of four common mood stabilizers—lithium, valproate, carbamazepine, and lamotrigine—on ADP proliferation, apoptosis, and differentiation. ADP proliferation, decreased by dexamethasone, was examined using Alamar Blue assay. Using TUNEL assay, ADP apoptosis induced by staurosporine was examined. The differentiated ADP induced by retinoic acid was characterized by immunostaining with anti-GFAP or anti-Tuj1 antibody. Lithium and valproate, but not carbamazepine and lamotrigine, recovered ADP proliferation decreased by dexamethasone. All four mood stabilizers decreased ADP apoptosis. Retinoic acid differentiated ADP into both neurons and astrocytes. Lithium and carbamazepine increased the ratio of neurons and decreased that of astrocytes. However, valproate and lamotrigine increased the ratio of astrocytes and decreased that of neurons. Therefore, these four stabilizers exhibited both common and differential effects on ADP proliferation, apoptosis, and differentiation.