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.