A new look at brain function and psychiatric disorders

Summary: Researchers have revealed the 3D structure of NMDA receptor molecules essential for brain health. NMDA receptors are thought to contribute to a range of neurological and psychiatric disorders, including schizophrenia, depression, stroke, and Alzheimer’s disease. The new model could aid in the development of new treatments for neuropsychiatric disorders.

Source: CSHL

New images from scientists at the Cold Spring Harbor Laboratory (CSHL) reveal for the first time the three-dimensional structures of a set of molecules essential for the proper functioning of the brain. The molecules are members of a family of proteins in the brain called NMDA receptors, which mediate the passage of essential signals between neurons.

The detailed images generated by the CSHL team will serve as a valuable model for drug developers working on new treatments for schizophrenia, depression and other neuropsychiatric disorders.

“This NMDA receptor is such an important drug target,” says Tsung-Han Chou, a postdoctoral researcher in the lab of Professor Hiro Furukawa at CSHL. Indeed, dysfunctional NMDA receptors are thought to contribute to a wide range of conditions, including not only depression and schizophrenia, but also Alzheimer’s disease, strokes and seizures.

“We hope that our images, which visualize the receptor for the first time, will facilitate drug development in the field based on our structural information,” says Chou.

NMDA receptors are found on neurons throughout the brain. When activated by a signaling molecule known as glutamate, one of many neurotransmitters in the brain, the receptor changes shape, opening a channel in the cell. This increases the likelihood of neurons sending a signal to neighboring cells.

Communication between neurons is essential for everything from movement to memory. Dysfunction and disease can occur when NMDA receptors cause too much or too little neural communication.

“GluN1-2C, GluN1-2A-2C, and GluN1-2D NMDA receptors exist in discrete brain regions, such as the cerebellum, at a defined period of brain development,” Furukawa explains.

“Abnormally low functioning NMDA receptors containing GluN1-2C are hypothesized to cause schizophrenia-like symptoms.”

While some NMDA receptor structures are better studied, less is known about those that Furukawa’s team focused on in their new study. A more complete picture was needed because the ability to target specific types of NMDA receptors would give pharmaceutical developers greater control over where in the brain a potential drug will be active.

And when it comes to developing better therapies, Chou says, “the more information we can get, the better.”

This shows a render of an NMDA receiver
A 3D atomic model of a variation of brain NMDA receptors, called the GluN1a-2C type. Targeting this type of receptor can help treat neuropsychiatric disorders like schizophrenia and Alzheimer’s disease. Credit: Furukawa Lab

Furukawa, Chou and their colleagues used a method called cryo-electron microscopy to capture a series of images of the receptors, which reveal their shapes in exquisite detail. Some images show the receptors grabbing glutamate, the natural neurotransmitter that activates them; others show receptors activated by a molecule used in the laboratory to enhance NMDA signaling.

By revealing exactly where and how these molecules interact, the new images will help guide the design of potential therapies that deactivate overactive NMDA receptors or activate those that are not sufficiently active.

About this neuroscience research news

Author: Samuel Diamond
Source: CSHL
Contact: Samuel Diamond – CSHL
Image: Image is credited to Furukawa Lab

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Original research: Access closed.
“Structural insights into the assembly and function of the NMDARs GluN1-2C, GluN1-2A-2C, and GluN1-2D” by Hiro Furukawa et al. molecular cell


Summary

Structural overview of the assembly and function of the NMDARs GluN1-2C, GluN1-2A-2C and GluN1-2D

Neurotransmission mediated by various subtypes of NOT-methyl-D-aspartate receptors (NMDARs) are fundamental for basic brain function and development as well as neuropsychiatric diseases and disorders. NMDARs are glycine- and glutamate-gated ion channels that exist as heterotetramers composed of obligate GluN1 and GluN2(AD) and/or GluN3(AB). GluN2C and GluN2D subunits form ion channels with distinct properties and spatiotemporal expression patterns.

Here we provide the structures of the agonist-bound human NMDAR GluN1-2C in the presence and absence of the selective positive allosteric potentiator of GluN2C (PAM), PYD-106, the tri-heteromeric NMDAR GluN1-2A-2C bound to agonist and agonist-bound GluN1-2D NMDARs by single-particle cryo-electron microscopy.

Our analysis shows unique inter-subunit and domain arrangements of GluN2C NMDARs, which contribute to functional regulation and PAM-binding pocket formation and are distinct from GluN2D NMDARs.

Our findings here provide the fundamental model for studying GluN2C and GluN2D-containing NMDARs, which are uniquely implicated in neuropsychiatric disorders.

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