How Are Memories Made?
Scientist Explains with Dr. Graham Collingridge
February 17, 2021
The brain has about 100 billion cells known as neurons. These neurons are all connected and “talk” to one other, which makes it possible for us to do our daily activities. In the brain, the place where one neuron ends and is connected to another neuron is called a synapse. A synapse is where neurons talk to one another.
At most synapses in the brain, the neurons talk to each other using a chemical known as a “neurotransmitter.” The most common neurotransmitter in the brain is known as L-glutamate. When one neuron talks to another, the first neuron releases L-glutamate into the synapse. The second neuron has proteins on its surface (called receptors) that are ready to receive the L-glutamate. Once the L-glutamate acts on the receptor, the second neuron receives the signal and becomes activated. The receptors involved in this process are known as AMPA receptors.
Canadian psychologist Donald Hebb proposed that learning is due to the strengthening of the synapses between the neurons in the brain in response to patterns of neural activity. Tim Bliss was a graduate student at McGill and when in search of so-called Hebbian synapses. In Oslo he found them by discovering the process known as long-term potentiation (LTP).
We now understand LTP at the molecular level. The synapse gets stronger because more AMPA receptors are inserted into the synapse leading to a bigger signal in the second neuron that is “listening”. This process is known as synaptic plasticity and is responsible for our learning. For instance, this process is involved when you can pick up playing piano more quickly after practicing, since the connections between the neurons that are active when you play piano are stronger.
The NMDA receptors, a second type of glutamate receptor, do not typically contribute to this communication. Instead they stay largely inactive until there is a period of more intense activity or talking between neurons. They are then temporarily awoken where they serve as the trigger for LTP, which is the process for how we form memories. This means at the level of the synapse, we can say that NMDA receptors are for learning and AMPA receptors are for memory.
Considerable work by many groups worldwide have built upon this simple concept and have shown that this type of mechanism occurs as we learn and remember. Notably, Richard Morris showed that blocking the NMDA receptors led to learning and memory problems in mammals.
This process is also key to understanding how the drug memantine (Namenda) works. This drug is the second class of drug approved by Health Canada for the treatment of Alzheimer’s disease and works by blocking the NMDA receptor.
Research has shown that not only blocking the NMDA receptor prevented LTP but also that over-stimulating the NMDA receptor prevented LTP. This latter process seems to occur in Alzheimer’s disease. By blocking the NMDA receptor in people living with Alzheimer’s disease with a drug like memantine, this can help to restore LTP when it is being prevented by over-stimulation of the NMDA receptor.
Unfortunately, however, memantine’s effectiveness is limited to a short-term improvement in thinking and memory and is only effective in some people living with Alzheimer’s disease. Ongoing research is currently looking into better ways to modify NMDA receptor activity and LTP to improve thinking and memory for longer periods of time and with fewer side effects.
