A New Look at Brain Function and Psychiatric Disorders

A New Look at Brain Function and Psychiatric Disorders

Summary: Researchers have discovered the 3D structure of NMDA receptor molecules that are critical to brain health. NMDA receptors are believed to contribute to a range of neurological and psychiatric disorders, including schizophrenia, depression, stroke and Alzheimer’s disease. The new model could help develop new treatments for neuropsychiatric disorders.

Source: CSHL

New images from Cold Spring Harbor Laboratory (CSHL) scientists reveal for the first time the three-dimensional structures of a set of molecules critical to healthy brain function. The molecules are members of a family of proteins in the brain known as NMDA receptors, which mediate the passage of important signals between neurons.

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

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

“We hope that our images, which visualize the receptor for the first time, will facilitate drug development across 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 the brain’s many neurotransmitters—the receptor changes shape, opening a channel into the cell. This increases the likelihood that neurons will fire a signal to neighboring cells.

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

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

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

While the structures of some NMDA receptors are better studied, less was known about the ones Furuka’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 manufacturers more control over where in the brain a potential drug would be active.

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

This shows a representation of the NMDA receptor
A 3D atomic model of a variation of NMDA brain receptors, called the GluN1a-2C type. Targeting this type of receptor may help treat neuropsychiatric disorders such as 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 how the receptors capture glutamate, the natural neurotransmitter that turns them on; 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 turn off overactive NMDA receptors or turn on those that are not active enough.

About this news about neuroscience research

Author: Samuel Diamond
Source: CSHL
Contact: Samuel Diamond – CSHL
picture: Image attributed to Furukawa Laboratory

See also

This shows a man running

Original Research: Closed access.
Structural insight into the assembly and function of GluN1-2C, GluN1-2A-2C and GluN1-2D NMDARs” by Hiro Furukawa et al. Molecular Cell


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

Neurotransmission mediated by different subtypes N-methyl-D-aspartate receptors (NMDARs) are fundamental to basic brain functions 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 different properties and spatiotemporal expression patterns.

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

Our analysis shows unique 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 a fundamental blueprint for studying GluN2C- and GluN2D-containing NMDARs, which are uniquely implicated in neuropsychiatric disorders.

#Brain #Function #Psychiatric #Disorders

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