Learning, Memory, and Long-Term Potentiation

All learning depends on memory.

• short-term memory.

  Humans undergoing electroshock treatment (to alleviate their depression) are unable to remember events that occurred just prior to the treatment, but their memory of earlier events is unimpaired.

  followed by formation of

• long-term memory. Damage to the temporal lobes of the brain can result in the loss of the ability to remember new learning for more than about an hour.

The study of long-term potentiation (LTP) provides a useful system in which to study the cellular and molecular basis for memory formation.

Rats and mice can be trained to solve simple tasks. For example, if a mouse is placed in a pool of murky water, it will swim about until it finds a hidden platform to climb out on. With repetition, the mouse soon learns to locate the platform more quickly. Presumably it does so with the aid of visual cues placed around the perimeter of the pool because it cannot see or smell the platform itself.

Rats or mice who have had a part of their brain called the hippocampus damaged, cannot learn this task, although they continue to solve it quickly if they were trained before their brain damage. This suggests that neurons in the hippocampus are needed for this type of learning.

Demonstrating Long-Term Potentiation

The behavior of certain synapses in the "CA1" region of the hippocampus of the rat (or mouse) is consistent with their being essential for this form of long-term memory.

Slices of the hippocampus can be removed and its CA1 neurons studied in vitro with recording electrodes. Rapid, intense stimulation of presynaptic neurons evokes action potentials in the postsynaptic neuron. This is just what we would expect from the properties of synapses.

What is remarkable about this system is that over time these synapses become increasingly sensitive so that a constant level of presynaptic stimulation becomes converted into a larger postsynaptic output (graph on right). This phenomenon, which can last for weeks, is called long-term potentiation (LTP).

Treatment of a slice of hippocampus with a drug called aminophosphonovaleric acid ("APV") prevents LTP. APV blocks the action of NMDA receptors, a subset of postsynaptic receptors that normally respond to the excitatory neurotransmitter glutamate (Glu).

NMDA receptors (synapse B above) are distinguished from other Glu-activated receptors in being stimulated by the drug, N-methyl-D-aspartate (NMDA).

NMDA receptors contain a transmembrane channel that allows for the facilitated diffusion of calcium ions (Ca²⁺) across the plasma membrane of the synapse. Binding of Glu (or NMDA) to these receptors opens the channel allowing Ca²⁺ to flow in

if and only if

the same postsynaptic cell has been simultaneously depolarized by other synapses on it (synapse A above).

The influx of Ca²⁺ into the neuron activates an enzyme called calcium-calmodulin-dependent kinase II (CaMKII). Kinases attach phosphate groups to proteins and, in so doing, alter their functioning. In this case, CaMKII phosphorylates a second type of Glu receptor called AMPA receptors, which makes them more permeable to sodium ions (Na⁺) thus lowering the resting potential of the cell and making it more sensitive to incoming impulses. In addition, there is evidence that the activity of CaMKII increases the number of AMPA receptors at the synapse.

The ability to make transgenic mice has provided tools to test this model of LTP.

This was shown (by A. J. Silver, et. al., in Science 257:206, 1992) in two ways:

• by measuring the current in the postsynaptic cell of normal mice and mutant mice. This graph (right) shows that mutant mice do not develop the increase in current flow that normal mice (above) do.
• The same failure of LTP occurs when the mice are tested on the hidden platform (left).

• greater post-synaptic currents in their hippocampus,
• their enhanced performance on the hidden-platform test,
• and enhanced performance in other tests of learning and memory.

Summary

• Rapid, intense stimulation of CA1 neurons in the hippocampus depolarizes them.
• Their NMDA receptors open.
• Ca²⁺ ions flow into the cell through the NMDA receptors and bind to calmodulin.
• This activates calcium-calmodulin-dependent kinase II (CaMKII).
  • CaMKII phosphorylates AMPA receptors making them more permeable to the inflow of Na+ ions and thus increasing the sensitivity of the cell to depolarization.
  • CaMKII may also increase the number of AMPA receptors at the synapse.
• Increased gene expression (i.e., protein synthesis - perhaps of AMPA receptors) also occurs during the development of LTP.

Long-Term Depression (LTD)

Slow, weak stimulation of CA1 neurons also brings about long-term changes in the synapses, in this case, a reduction in the sensitivity. This is called long-term depression or LTD.