Calcium-induced neuronal degeneration: a normal growth cone regulating signal gone awry (?)

The neuronal growth cone is involved in neurite elongation, directional pathfinding, and target recognition. These activities are essential for proper assembly of functional circuits within the developing nervous system, for regeneration of functional circuitry following damage, and also, perhaps, for remodeling of the nervous system in response to environmental stimuli. Our studies of both molluscan and mammalian neurons in culture have shown that neurite outgrowth can only proceed when intracellular calcium levels lie within a specific outgrowth-permissive range. Cessation of outgrowth can be induced by a variety of signals normally used for communication within the adult nervous system, including neurotransmitters, and action potentials; all of these signals elevate levels of intracellular calcium above the outgrowth-permissive range. For example, glutamate, whether added to the medium or released from co-cultured entorhinal explants, can selectively inhibit dendritic outgrowth. Conversely, inhibitory neurotransmitters can block the outgrowth-inhibitory effects of glutamate and actually promote expansion of dendritic arbors. Dendritic outgrowth is therefore regulated by a balance between excitatory and inhibitory neurotransmitter activity. Extreme excitatory imbalance in neurotransmitter input to pyramidal neurons causes cell death. Each of these changes in neuroarchitecture is mediated by changes in levels of intracellular calcium. We therefore put forward the hypothesis that key mechanisms which normally control the development and plasticity of neural circuitry, are also involved in neurodegeneration. Local, moderate elevations in calcium result in dendritic pruning. Higher, global elevations in calcium result in cell death. This cell death may serve an important function during normal development; aging may result in the same mechanism being employed pathologically. When intracellular calcium levels are not regulated within normal limits, as may occur in aging, neurodegeneration may occur.