Long-Term Potentiation: Learning About How We Learn

Updated: Apr 8, 2020

By Chris Jung

The ability to store memories and build on them is a key proponent of mammalian life: one that certainly served our early ancestors well and is a fundamental aspect of learning. This stems from synaptic plasticity: a neuron’s ability to modify the strength and efficacy of synaptic transmission through a diverse number of activity-dependent mechanisms.

Long-term potentiation and long-term depression are crucial for synaptic plasticity; defined as the ability to strengthen connections in our synapses and weaken them, respectively. And although this concept seems to be a basic cornerstone in neurology research, like anything in the field of modern neuroscience, it wasn’t that long ago when this process of learning was completely ambiguous. As with all science, the validity of these theories should always be kept in consideration.

1906 Nobel Prize Laureate Santiago Ramón y Cajal was among the first to theorize that learning didn’t involve the formation of new synapses. A few decades later, Canadian psychologist Donald Hebb formed his distinguished Hebb’s postulate, which is often summarized into the phrase “neurons that fire together, wire together,” forming the basis of Hebbian learning in which increased stimulation increases synaptic strength (for machine learning enthusiasts: learn about unsupervised learning/neural networks based on this concept). Long-term potentiation, or LTP, was first observed in the rabbit hippocampus in 1973 by Terje Lømo and Timothy Bliss in the University of Oslo. (They were able to show that a burst of stimulus on perforant path fibres led to a long-lasting change in the postsynaptic response of cells in the dentate gyrus. Their studies also revolutionized the hippocampus as a place of memory storage).

While LTP has been identified in other regions of the brain, it has been extensively studied in the Schaffer collaterals, the axons comprising the synapse between glutaminergic CA3 and CA1 neurons in the hippocampus. Potentiation in this region of the brain involves the NMDA (N-Methyl-d-aspartate) receptor, but it is not the only receptor involved in LTP. For example, in the preceding mossy fibers between the dentate gyrus and the CA3 neurons, the G-protein linked metabotropic glutamate receptors are the primary receptors.

Nonetheless, these receptors bind to glutamate, our brain’s most common excitatory neurotransmitter. (More on neurotransmission will be posted in a future article). Glutamate has several fast excitatory ionotropic receptors: transmembrane proteins permeable to certain ions that simply rely on a first messenger as the trigger to open.

In postsynaptic CA1 neurons, glutamate binds to two of its excitatory ionotropic receptors, NMDA (N-Methyl-d-aspartate) and AMPA ( α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. NMDA receptors are non-selectively cationic: that is, they are permeable to calcium, and AMPA receptors are selectively cationic, permeable to both to Na+ and K+.

When some outer stimulus is triggered, a neuron is fired, and glutamate is released from the CA3 axon terminal and binds to the NMDA and AMPA receptors. The AMPA receptors open immediately, letting in Na+ and allowing K+ to flow out as they move down their membrane potentials (again, will be explained in a future post). The NMDA receptors open (they also require a glycine along with the glutamate), but ion movement is blocked by a positively charged magnesium ion acting as a voltage sensor.

This is where the aspect of learning comes in. Say you are studying for an upcoming history test and make a flashcard that says the War of 1812 ended in 1815 (if you include the Battle of New Orleans). If you review your flashcard briefly, your neuron will fire once, allowing for the AMPA receptors to open but the Ca2+ influx being inhibited by the Mg2+ ion.