A new perspective on brain function and mental disorders

New images from scientists at Cold Spring Harbor Laboratory (CSHL) reveal for the first time the three-dimensional structure
of a group of molecules that are essential for healthy brain function.
These molecules are members of a family of proteins in the brain called NMDA receptors, which regulate the transmission
of basic signals between neurons.
The detailed images generated by the CSHL team will provide a valuable blueprint
for drug developers working on new treatments for schizophrenia, depression, and other neuropsychiatric disorders.

"This NMDA receptor is a very important drug target," said
Tsung-Han Chou, a postdoctoral researcher in the lab of CSHL professor Hiro Furukawa.
That's because dysfunctional NMDA receptors are thought to be linked to a variety of conditions, including not only depression and schizophrenia, but also Alzheimer's disease, stroke, and epilepsy
.
"We hope that our images, visualizing the receptor for the first time, will facilitate drug development
across the field based on our structural information," Chou said.

NMDA receptors are found in
neurons throughout the brain.
When activated by a signaling molecule called glutamic acid, the receptor changes shape and opens a pathway
into the cell.
Glutamate is a neurotransmitter in the brain
.
This increases the likelihood that
neurons will signal neighboring cells.
Communication between neurons is essential
for everything from movement to memory.
When NMDA receptors cause too much or too little neural communication, it leads to dysfunction and disease
.

"GluN1-2C, GluN1-2A-2C, and GluN1-2D NMDA receptors are present in discrete brain regions, such as the cerebellum, during specific periods of brain development," Furukawa explains
.
"It has been hypothesized that abnormally low NMDA receptors containing GluN1-2C can cause schizophrenia-like symptoms
.
"

While the structure of some NMDA receptors has been better studied, the structures of those that the Furukawa team focused on in their new study are poorly
understood.
A more complete picture is needed because the ability to target specific types of NMDA receptors will give drug developers more control over where in the brain a potential drug works
.
When it comes to developing better therapies, Chou says, "The more information we get, the better
.
" ”

Furukawa, Chou and their colleagues used cryo-electron microscopy to capture a series of images of the receptors that precisely revealed their shape
.
Some images show receptors grasping glutamate, a natural neurotransmitter, that makes them start; Others show receptors
activated by molecules used in the lab to enhance NMDA signaling.
By revealing exactly where and how these molecules interact, the new picture will help guide the design of potential therapies that turn off overactive NMDA receptors or turn on those that are less active
.

Structural insights into assembly and function of GluN1-2C, GluN1-2A-2C, and GluN1-2D NMDARs