Persistent stimulation at the neuronal synapse can lead to markedly different outcomes for the post-synaptic neuron. Extended weak signaling can result in long-term depression (LTD), in which activation of the post-synaptic neuron requires a stronger signal than before LTD was initiated. In contrast, long-term potentiation (LTP) occurs when the post-synaptic neuron is subjected to a strong stimulus, and this results in strengthening of the neural synapse (i.e., less neurotransmitter signal is required for activation).
In the CA1 region of the hippocampus, the decision between LTD and LTP is mediated solely by the level of intracellular  at the post-synaptic dendritic spine. Low levels of  (resulting from low-level stimulation) activates the protein phosphatase calcineurin, which induces LTD. Higher levels of  results in activation of /calmodulin-dependent protein kinase II (CaMKII), which leads to LTP. The difference in Ca concentration required for a cell to undergo LTP is only marginally higher than for LTD, and because neurons show bistability (either LTP or LTD) following persistent stimulation, this suggests that one or more components of the system respond in a switch-like, or ultrasensitive manner. Bradshaw et al. demonstrated that CaMKII (the LTP inducer) responds to intracellular calcium levels in an ultrasensitive manner, with <10% activity at 1.0 uM and ~90% activity at 1.5 uM, resulting in a Hill coefficient of ~8. Further experiments showed that this ultrasenstivity was mediated by cooperative binding of CaMKII by two molecules of calmodulin (CaM), and autophosphorylation of activated CaMKII leading to a positive feedback loop.
In this way, intracellular calcium can induce a graded, non-ultrasensitive activation of calcineurin at low levels, leading to LTD, whereas the ultrasensitive activation of CaMKII results in a threshold intracellular calcium level that generates a positive feedback loop that amplifies the signal and leads to the opposite cellular outcome: LTP. Thus, binding of a single substrate to multiple enzymes with different sensitivities facilitates a bistable decision for the cell to undergo LTD or LTP.