Researchers uncover the fundamental importance of AMPA receptor biogenesis for brain function

July 7, 2017, Albert Ludwigs University of Freiburg
Schematic illustration of AMPA receptor biogenesis in the endoplasmic reticulum (ER) with subsequent delivery to the synaptic compartment. Upper right: pedigree of one of the discovered FRRS1I families. Graphics: Bernd Fakler. Credit: Albert-Ludwigs-Universität Freiburg

For the first time, researchers have uncovered the significance of the molecular assembly processes—called biogenesis—of AMPA-type glutamate receptors for proper operation of the human brain. AMPA receptors, the most abundant neurotransmitter receptors in the brain, are multi-protein complexes that are assembled intracellularly and are subsequently transported to the synapses where they are responsible for signal transduction and information processing. Defective receptor assembly resulting from genetic mutations causes severe intellectual disability with cognitive impairment and epileptic activity. The results introduce an unexpected mechanism for the control of higher brain functions in humans. The biologists and geneticists recently published their findings in the online-journal Nature Communications.

Using high-resolution proteomic analysis, the scientists identified a population of AMPA in brain membrane preparations that fundamentally differs in their subunit composition from synaptic AMPA receptors. These newly identified complexes are restricted to the endoplasmic reticulum and represent a transitional step in the biogenesis of synaptic receptor complexes.. When formation of these transitional complexes is inhibited via virus administered to rodent brain, the number of synaptic AMPA receptors is drastically reduced. As a result, the researchers detected a largely disturbed synaptic signal transduction.

In the , impairment of AMPA receptor biogenesis may be invoked by mutations in the main subunit of the transitional complexes, the so-called FRRS1I . The researchers identified there different FRRS1l mutations in three distinct families where homozygously affected patients (mutations in both, maternal and paternal alleles) suffered from severe brain dysfunction: all patients demonstrated largely impaired intellectual abilities, delayed or complete lack of speech development and . Interestingly, the diseased brains failed to show any significant alterations in morphology. For the scientists, these observations are indicative for functional deficiencies induced by the impaired AMPA receptor biogenesis as the disease-causing mechanism.

As early as 2012, Bernd Fakler's group has shown that AMPA receptors in the brains are assembled from an array of more than 30 different proteins. Quite a number of these proteins—including the FRRS1I protein—lack annotation of primary function(s). With their current work, the scientists have shown how important these 'unknown' protein components and research pursuing their molecular mode of action are for understanding higher functions.

Explore further: The spatial and temporal dynamics of specific glutamate receptors in the brain

More information: Aline Brechet et al. AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability, Nature Communications (2017). DOI: 10.1038/NCOMMS15910

Related Stories

The spatial and temporal dynamics of specific glutamate receptors in the brain

October 6, 2014
Dr. Uwe Schulte, Dr. Jochen Schwenk, Prof. Dr. Bernd Fakler, and their team have elucidated the enormous spatial and temporal dynamics in protein composition of the AMPA-type glutamate receptors, the most important excitatory ...

Detailed images reveal interactions that affect signaling in the brain

May 3, 2017
Scientists at Columbia University have obtained the first detailed images of interactions between the AMPA receptor and molecules that regulate chemical signaling in the brain. Their findings may help understand the processes ...

Brain study reveals how long-term memories are erased

March 31, 2016
Vital clues about how the brain erases long term memories have been uncovered by researchers.

What makes the brain tick so fast? Study sheds light on the workings of brain neurotransmitter receptors

February 25, 2016
Surprisingly complex interactions between neurotransmitter receptors and other key proteins help explain the brain's ability to process information with lightning speed, according to a new study.

Scientists learn more about how inhibitory brain cells get excited

January 30, 2013
Scientists have found an early step in how the brain's inhibitory cells get excited.

Team explains how mutated X-linked mental retardation protein impairs neuron function

June 24, 2014
There are new clues about malfunctions in brain cells that contribute to intellectual disability and possibly other developmental brain disorders.

Recommended for you

Do you see what I see? Researchers harness brain waves to reconstruct images of what we perceive

February 22, 2018
A new technique developed by neuroscientists at the University of Toronto Scarborough can, for the first time, reconstruct images of what people perceive based on their brain activity gathered by EEG.

Neuroscientists discover a brain signal that indicates whether speech has been understood

February 22, 2018
Neuroscientists from Trinity College Dublin and the University of Rochester have identified a specific brain signal associated with the conversion of speech into understanding. The signal is present when the listener has ...

Study in mice suggests personalized stem cell treatment may offer relief for multiple sclerosis

February 22, 2018
Scientists have shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, help reduce inflammation and may be able to help repair damage caused by multiple sclerosis ...

Biomarker, clues to possible therapy found in novel childhood neurogenetic disease

February 22, 2018
Researchers studying a rare genetic disorder that causes severe, progressive neurological problems in childhood have discovered insights into biological mechanisms that drive the disease, along with early clues that an amino ...

A look at the space between mouse brain cells

February 22, 2018
Between the brain's neurons and glial cells is a critical but understudied structure that's been called neuroscience's final frontier: the extracellular space. With a new imaging paradigm, scientists can now see into and ...

Nolan film 'Memento' reveals how the brain remembers and interprets events from clues

February 22, 2018
Key repeating moments in the film give viewers the information they need to understand the storyline. The scenes cause identical reactions in the viewer's brain. The results deepen our understanding of how the brain functions, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.