Brain molecule that makes neurons less selective could deepen understanding of human cognition

Neuroscientists at Johns Hopkins Medicine say they have determined how a molecule on the surface of brain cells shapes the behavior of certain neurons.

The research, published October 2 in Naturereveals how a molecule, permeable calcium (CP)-AMPA receptor, suppresses a specific neuron’s ability to pay attention to specific external cues, such as your friend’s earrings, according to the study genetically modified mice.

Understanding why some neurons are less “selective” in their response to certain signals could also help researchers study schizophrenia, epilepsy and autism, conditions marked by faulty processing of external signals and failures in the functioning of neurons. neurons in the mammalian brain.

“We found that the calcium-permeable subtype of AMPA receptors plays an additional role in suppressing the selectivity of a given neuron,” says Ingie Hong, Ph.D., first author and instructor of neuroscience at Medicine from Johns Hopkins University.

“Until now, the role of these specific receptors in the broader mammalian brain, as it functions in daily life, remained a mystery.”

Along with Hong, the research was led by Richard Huganir, Ph.D., Bloomberg Distinguished Professor of Neuroscience and Psychological and Brain Sciences and chair of the Solomon H. Snyder Department of Neuroscience at Johns Hopkins University School of Medicine, who has been studying AMPA receptors for over 40 years.

AMPA receptors are essential for rapid information transfer and memory formation in the brain, such as hearing and remembering a person’s name. The AMPA receptor subtype in this study, CP-AMPA receptors, acts as a “gate” that decreases the selectivity of parvalbumin (PV) neurons, which are inhibitory and thus exert non-selective inhibition on neighboring neurons, say the researchers.

“Selective neurons will respond to something really specific, for example your grandfather’s mustache, while less selective neurons will also respond to different faces or people,” says Hong.

“We investigated the mechanisms and molecules that control this specificity, or selectivity, and how it goes wrong in conditions such as autism and epilepsy, where excitatory neurons can become overstimulated.”

Researchers also found that mutations in GluA2, a protein subunit of the CP-AMPA receptor, are associated with intellectual disability.

“Human mutations in the GluA2 subunit of AMPA receptors, which regulate the calcium permeability of the receptor, can lead to intellectual disability and autism,” explains lead author Huganir. “This suggests that tight control of calcium permeability of AMPA receptors is essential for human cognition.”

Specifically, the researchers focused on CP-AMPA receptors in two distinct areas of the brain, the visual cortex, where neurons process visual information, and the hippocampus, where neurons respond to “where you are, where you go or wherever you have.” ” said Hong.

To conduct their research, the scientists developed new adeno-associated viral vectors to replace calcium-permeable AMPA receptors with impermeable counterparts and express them in the mouse brain. They say they hope these vectors can help treat disorders resulting from AMPA receptor mutations in the future.

To map the selectivity of PV neurons, scientists used advanced imaging techniques to observe the structure and activity of neurons deep in the brains of genetically modified mice while showing them video stimuli.

“In most cases, we found that these PV neurons, which are generally less selective, became more selective to visual stimuli as well as spatial location when we replaced the CP-AMPA receptors with impermeable molecules, which which allowed inhibitory neurons to act more like excitatory neurons,” Hong said.

The researchers say that the large amount of CP-AMPA receptors in PV neurons is well conserved in many mammalian species, including humans.

“Making neuron inhibition less selective makes our neural circuits more efficient than species that do not have this molecular feature,” Hong explains. “It probably also means that our neural networks are more stable.”

Hong says the new research could also have implications for machine learning used in artificial intelligence.

“In machine learning, there are many computerized ‘artificial’ neurons that are trained to be very or less selective,” he explains. “We’re trying to figure out how specific and less specific units can work together to give us smarter machines and AI.”

Next, the scientists intend to study other critical molecules known to modify cognition. In clinical neuroscience, Hong says, a better understanding of the brain molecules that contribute to biased neural calculations in patients could advance the search for therapeutic drug targets in psychiatric disorders with a genetic component, a nascent field that Hong calls “neurocomputational therapy.” .