Could a novel mechanism for synaptic plasticity hold potential for new epilepsy treatment?

Written by Kimberley Ndungu (Future Science Group)

The AMPA receptor plays a crucial role in memory and learning, however, it is not yet fully understood how these receptors form and work.

Therefore, a team of researchers from the Membrane Cooperativity Unit at the Okinawa Institute of Science and Technology Graduate University (Japan), in collaboration with other universities across Japan, used fluorescent tags to investigate AMPA receptors.

In the study published in Nature Communications, the researchers discovered that rather than existing as stable entities, AMPA receptors continually form and disintegrate.

AMPA receptors are composed of four subunits (GluA1, 2, 3, and 4) and different combinations of subunits form tetramers, resulting in 256 possible configurations of the receptor.

It was believed that these tetramers originate from the endoplasmic reticulum and then migrate to the synapse, while retaining a stable structure.

“This tetramer stability could actually be problematic for neurons,” commented co-author of the study, Akihiro Kusumi (Okinawa Institute of Science and Technology Graduate University). “The synapses need AMPA receptor tetramers with different combinations of subunits as the brain learns and its neuronal circuits change. Thus, we had a gut feeling that something was terribly wrong with the accepted notion of how AMPA receptors form, migrate, and work.”

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The team tracked the movement of the molecule in living cells using a single-molecule fluorescent microscope and software. The researchers observed that the molecules jostled around in the membrane as single molecules, as well as in assemblies of twos, threes and fours.

Tetramers were discovered to work as small channels for less than 0.1 seconds, however, fell apart within 0.1–0.2 seconds. Then the separated molecules found new partner molecules to form new assemblies with and continually repeated this process.

This process allows for AMPA receptors with different subunit compositions to readily form, demonstrating a novel mechanism for synaptic plasticity.

These findings may represent the early stages of synaptic plasticity that is essential for memory and learning, and could have pharmacological applications in the treatment of epilepsy.

Current treatments for epilepsy include anticonvulsants that stop glutamate from binding to AMPA receptor tetramers, however, these treatments can be ineffective.

Kusumi believes the development of drugs that slow down the process that forms tetramers, observed in this study, could mitigate problematic types of synaptic plasticity, resulting in reduced symptoms of epilepsy.