calcium channels in the axon and terminal. As the frequency of stimuli increases, there is less time between each stimulus for the cell to repolarize and return to normal resting potential. Therefore, the resting potential becomes more depolarized, meaning a smaller depolarizing current is needed to fire an action potential. However, this modulation is usually very short lived. If the stimulation ceases, the neuron will revert to its original resting potential as the ion channels and pumps have ample time to recover from the last stimulus. Long-term effects: High frequency stimulation of a neuron over a long period of time causes two resulting neuronal changes. Initially, the neuron responds as it would during short-term stimulation, with an increase in excitability. Continuing the high frequency stimulation after this point, results in a drastic, non-reversible change in excitability. When sodium concentrations reach a high enough level in the axon, sodium/calcium pumps reverse their direction of flow, causing calcium to be imported into the cell as sodium is exported out. The increased calcium concentration (and subsequent depolarization of the membrane) inactivates sodium channels and targets them for endocytosis and lysosomal hydrolysis. This results in a major decrease in axonal sodium channels, which are necessary for action potential propagation. If the stimulation continues, eventually the neuron will stop transmitting action potentials and will die. Neuronal death due to overstimulation is called excitotoxicity. Low frequency stimulation Short-term effects: All living neurons have a basal rate of action potential propagation and synaptic release. Thus, low frequency stimulation of a neuron in the short term is similar to the activity of a neuron at rest in the brain. No major changes happen to the intrinsic excitability of the neuron. Long-term effects: Low frequency stimulation of a neuron for a long period of time decreases the excitability of the neuron by activating calcium-dependent phosphatases that tag AMPA receptors for internalization. Low frequency stimulation leads to low levels of calcium in the cell. When calcium concentrations are low, active calcium-dependent phosphatases dominate over calcium-dependent kinases. As more phosphatases are activated, they tag more AMPA receptors for internalization through endocytosis. Since AMPA receptors are one of the main excitatory receptors on neurons, removing them from the cell membrane effectively depresses the cell (if the cell cannot react to excitatory signals, it cannot generate an action potential of its own). In this way low frequency stimulation can actually reverse the effects