Long-term depression · Grey Matter

Long-term depression (LTD) is a lasting decrease in the strength of a synapse, produced by weak or poorly timed activity, and it is the counterpart that lets learning erase and refine as well as add.

Long-term depression. Long-term depression (LTD) is a lasting decrease in the strength of a synapse, produced by weak or poorly timed activity, and it is the counterpart that lets learning erase and refine as well as add.

The standard way to induce it in the hippocampus is prolonged low-frequency stimulation, for example 900 pulses at 1 Hz, which leaves a synapse weaker for hours. At many synapses it starts at the same NMDA receptor as LTP, with a different calcium signal: a modest, prolonged rise instead of a large, brief one. That level of calcium favours protein phosphatases (calcineurin and protein phosphatase 1) over kinases; they dephosphorylate AMPA receptors and trigger their removal from the synapse by endocytosis, so the same glutamate produces a smaller current. Other forms rely on metabotropic glutamate receptors or on endocannabinoids acting on the presynaptic terminal.

The direction of change follows calcium. A large, fast rise gives LTP, a moderate sustained one gives LTD, and very low calcium gives neither; this calcium-threshold picture explains why the same synapse can move both ways.

It is how the cerebellum learns. At the synapses of parallel fibres onto Purkinje cells, LTD driven by error signals from climbing fibres is a classic mechanism of motor learning.

It keeps the system in range. Without a way down, repeated LTP would saturate synapses and erase the differences that store information.

LTD is the eraser that makes learning selective.

A memory is a pattern of strong and weak synapses, and the weak ones have to be made as deliberately as the strong.

Questions: How can the same NMDA receptor make a synapse stronger or weaker? Both directions start with calcium entering a spine through NMDA receptors, and the pattern of that calcium decides which way the synapse goes. A large, fast rise, produced by strong coincident activity such as a high-frequency burst, activates kinases (above all CaMKII) that add and strengthen AMPA receptors, which is LTP. A modest, prolonged rise, produced by low-frequency activity such as 900 pulses at 1 Hz, favours phosphatases that dephosphorylate AMPA receptors and pull them out of the membrane, which is LTD. NMDA receptor blockers prevent both, which is how Dudek and Bear showed in 1992 that this form of LTD needs the same receptor as LTP.