Structure of hippocampal AMPA receptor assemblies involved in memory and learning

Structure of hippocampal AMPA receptor assemblies involved in memory and learning

Scientists have for the first time revealed the structure surrounding important receptors in the brain's hippocampus, the seat of memory and learning. The study was published in the journal Nature.

The new study focuses on the organization and function of glutamate receptors, a type of neurotransmitter receptor involved in sensing signals between nerve cells in the hippocampus region of the brain. The study reveals the molecular structure of three major complexes of glutamate receptors in the hippocampus.

The findings may be immediately useful in drug development for conditions such as epilepsy, said the senior author.

"Epilepsy or seizure disorders can have many causes," the author said. "If one knows the underlying cause for a particular person's seizure activity, then you may be able to develop small molecules to modulate that activity."

Working with a mouse model, the researchers made the breakthrough by developing a chemical reagent based on monoclonal antibodies to isolate the receptor and the complex of subunits surrounding it. They then imaged the assemblage using state-of-the-art cryo-electron microscopy.

The GluA1–GluA2, GluA1–GluA2–GluA3 and GluA2–GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2–SynDIG4 non-stochastically positioned at the B′/D′ and A′/C′ positions, respectively.

The authors further demonstrate how the receptor–TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor.

"It really opens the door to specifically target the molecules that need to be targeted in order to treat a particular condition," the author said. "A great deal of drug development is structure-based, where you see what the lock looks like and then you develop a key. If you don't know what the lock looks like, then it's much harder to develop a key."

Previously, scientists had to rely on mimicking the actual receptors by artificially engineering receptors by combining DNA segments in tissue culture. However, that technique has obvious shortcomings.

"It doesn't work perfectly because the real receptors are surrounded by a constellation of additional, sometimes previously unknown, subunits," the senior author said.
The new monoclonal antibody reagents enabled scientists to isolate actual glutamate receptors from the brain tissue of mice. They then were able to image those samples in near-atomic detail using cryo-EM, which allowed them to capture the entire assemblage of three types of glutamate receptors along with their auxiliary subunits.

"Previously, it's been impossible to do this because we had no good way to isolate molecules and no way to see what they looked like," the author said. "So this is a super exciting development."