Lithium Induces Apoptosis in Immature Cerebellar Granule Cells but Promotes Survival of Mature Neurons

Lithium (Li⁺) has been used in the treatment of manic—depressive disorders for several decades. More recently, Li⁺ has been shown to affect the signaling pathway of various neurotransmitters and growth/neurotrophic factors. We examined the effect of Li⁺ on the survival of cerebellar granule neurons in culture. Treatment of immature granule cells with Li⁺ resulted in programmed cell death (apoptosis). The death process is accompanied by DNA fragmentation, a hallmark of apoptosis. Following maturation in vitro, granule neurons are dependent on elevated concentrations of extracellular potassium (K⁺]_o) for survival. Lowering of K⁺]_o to physiological levels induces apoptosis. Surprisingly, Li⁺ prevents death of mature neurons caused by low K⁺]_o. Moreover, the concentration range at which Li⁺ exerts its protective effect is the same as that at which it induces apoptosis in immature neurons. Thus, a single agent under similar extracellular conditions has opposing effects on survival, depending on the developmental status of the neuron.