Long-term depression, or LTD, is one of the ways by which synaptic plasticity—changes in the strength of chemical synapses—can occur in the brain. LTD is the process of synaptic weakening that occurs over time between pre and postsynaptic neuronal connections. The synaptic weakening of LTD works in opposition to synaptic strengthening by long-term potentiation (LTP) and together are the main mechanisms that underlie learning and memory.

Calcium Ion Concentration Mechanism

If over time, all synapses are maximally strengthened through LTP or some other mechanism, the brain would plateau in efficiency, making learning and forming new memories difficult. LTD is a way to prune weaker synapses thereby freeing up resources and putting flexibility back into the central nervous system. One mechanism by which LTD occurs depends on the number of calcium ions in the postsynaptic neuron after presynaptic stimulation. Infrequent or low levels of presynaptic stimulation lead to low calcium ion influx and consequently, low calcium ion concentration in the postsynaptic neuron.

The low calcium ion concentration initiates a signaling cascade that culminates in the endocytosis or removal of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors from the plasma membrane. As a result, the postsynaptic response to the same sporadic presynaptic stimulation is further weakened, since there are fewer channels for positively charged ions to enter and depolarize the membrane. The neuron reuses the AMPA receptors at a later time and/or separates them into their constituent subunits.

LTD was first described as occurring in the hippocampus, where it is thought to clear old memories. Subsequently, LTD has been shown to occur in many brain regions such as the cerebellum, striatum, and cortex. The ubiquitous presence of LTD underlies its importance in proper brain functioning.

LTD and Disease

Malfunctioning mechanisms of LTD are thought to contribute to numerous neurological and cognitive disorders such as addiction, mental retardation, and Alzheimer's disease. Research is ongoing to better understand the mechanisms of LTD, how neurological disorders occur, and to develop treatments.