LTD occurs at synapses in cerebellar Purkinje neurons, which receive two forms of excitatory input, one from a single climbing fiber and one from hundreds of thousands of parallel fibers. LTD decreases the efficacy of parallel fiber synapse transmission, though, according to recent findings, it also impairs climbing fiber synapse transmission. Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur. With respect to calcium release however, it is best if the parallel fibers are activated a few hundred milliseconds before the climbing fibres. In one pathway, parallel fiber terminals release glutamate to activate AMPA and metabotropic glutamate receptors in the postsynaptic Purkinje cell. When glutamate binds to the AMPA receptor, the membrane depolarizes. Glutamate binding to the metabotropic receptor activates phospholipase C (PLC) and produces diacylglycerol (DAG) and inositol triphosphate (IP3) second messengers. In the pathway initiated by activation of climbing fibers, calcium enters the postsynaptic cell through voltage-gated ion channels, raising intracellular calcium levels. Together, DAG and IP3 augment the calcium concentration rise by targeting IP3-sensitive receptors triggering release of calcium from intracellular stores as well as protein kinase C (PKC) activation (which is accomplished jointly by calcium and DAG). PKC phosphorylates AMPA receptors, which promotes their dissociation from scaffold proteins in the post-synaptic membrane and subsequent internalization. With the loss of AMPA receptors, the postsynaptic Purkinje cell response to glutamate release from parallel fibers is depressed. Calcium triggering in the cerebellum is a critical mechanism involved in long-term depression. Parallel fibre terminals and climbing fibres work together in a positive feedback loop for invoking high calcium release. LTD is involved in predictive control exerted by cerebellar circuitry and cerebellar reserve.