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

Hebbian LTP

LTP can occur when presynaptic neurons repeatedly fire and stimulate the postsynaptic neuron. This is called Hebbian LTP since it follows from Donald Hebb’s 1949 postulate that “neurons that fire together wire together.” The repeated stimulation from presynaptic neurons induces changes in the type and number of ion channels in the postsynaptic membrane.

Two types of postsynaptic receptors of the excitatory neurotransmitter glutamate are involved in LTP: 1) N-methyl-D-aspartate or NMDA receptors and 2) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or AMPA receptors. Although NMDA receptors open upon glutamate binding, their pore is usually blocked by magnesium ions that prevent other positively charged ions from entering the neuron. However, glutamate released from presynaptic neurons can bind to postsynaptic AMPA receptors, causing an influx of sodium ions that results in membrane depolarization. When the postsynaptic membrane is depolarized by multiple frequent presynaptic inputs, the magnesium ion blocking the NMDA receptor pore is displaced, allowing sodium and calcium ions to flow into the neuron.

The increased calcium ion influx then initiates a signaling cascade that culminates in more AMPA receptors being inserted into the plasma membrane. Alternatively, the signaling cascade may phosphorylate glutamate receptors—enabling them to stay open for a longer duration and enhancing the conductance of positively charged ions into the cell. As a result, the same presynaptic stimulation will now evoke a stronger postsynaptic response given that more glutamate receptors will be activated and more positively charged ions will enter the postsynaptic neuron. The amplification that occurs is known as synaptic strengthening or potentiation.

The adage “practice makes perfect” can be partly explained by LTP. When a novel task is being learned, new neural circuits are reinforced using LTP. After each iteration of practice, the synaptic strength in the neural circuits become stronger, and soon the task can be performed correctly and efficiently. The newly strengthened connections can last from minutes to weeks or longer if the presynaptic stimulation persists, meaning that each subsequent time the task is performed the LTP is maintained.

LTP and Disease

When LTP functions normally, we can learn and form memories with ease. However, abnormalities in LTP have been implicated in many neurological and cognitive disorders such as Alzheimer’s disease, autism, addiction, schizophrenia, and multiple sclerosis. A better understanding of the mechanisms behind LTP could eventually lead to therapies.