Researchers at Johns Hopkins Medicine have uncovered how a specific molecule on the surface of brain cells influences the behavior of certain neurons.
According to a study published on October 2 in Nature, the calcium permeable (CP)-AMPA receptor plays a significant role in reducing a neuron’s ability to focus on specific external signals, like noticing your friend’s earrings. The study, conducted in genetically modified mice, suggests that understanding why some neurons are less selective in responding to particular cues could aid in researching conditions such as schizophrenia, epilepsy, and autism, which are characterized by improper processing of external stimuli and irregular neuronal firing in the mammalian brain.
“We’ve found that the calcium permeable type of AMPA receptors has an additional function that diminishes the selectivity of certain neurons,” explains Ingie Hong, Ph.D., the lead author and an instructor in neuroscience at Johns Hopkins University Medicine. “Previously, the specific roles of these receptors in the broader mammalian brain during daily functions have remained unclear.”
The research was spearheaded by Richard Huganir, Ph.D., a Bloomberg Distinguished Professor of Neuroscience and Psychological and Brain Sciences, who has dedicated over 40 years to studying AMPA receptors.
AMPA receptors are essential for rapid information transmission and memory formation in the brain, such as recognizing and recalling a person’s name. In this research, the CP-AMPA receptors act as a “gate” that lessens the selectivity of parvalbumin (PV) neurons, known for their inhibitory functions, thereby causing a non-selective inhibition of nearby neurons.
“Selective neurons react to very specific stimuli, like your grandfather’s mustache, while less selective neurons may respond to various faces or individuals,” Hong states. “We’ve been exploring the mechanisms and molecules that define this selectivity and how it may go awry in conditions like autism and epilepsy, where excitatory neurons can be excessively stimulated.”
The researchers also observed that mutations in GluA2, a protein component within the CP-AMPA receptor, correspond with intellectual disabilities.
“Mutations in the GluA2 subunit of AMPA receptors, which helps regulate the receptor’s calcium permeability, can lead to intellectual disabilities and autism,” adds senior author Huganir. “This indicates that maintaining strict control of AMPA receptor calcium permeability is vital for human cognitive function.”
Specifically, the team examined CP-AMPA receptors in two important areas of the brain: the visual cortex, responsible for processing visual information, and the hippocampus, which contributes to an understanding of one’s location and past experiences, according to Hong.
To carry out their study, the scientists created new adeno-associated virus vectors to substitute calcium permeable AMPA receptors with impermeable versions within the mouse brain. They believe these vectors could potentially aid in treating disorders linked to AMPA receptor mutations in the future.
Utilizing advanced imaging techniques, the scientists mapped out the selectivity of PV neurons by observing their structure and activity deep within the brains of genetically engineered mice exposed to video stimuli.
“In most instances, we discovered that these PV neurons, which usually lack selectivity, became more discerning towards visual stimuli and spatial locations when we replaced CP-AMPA receptors with impermeable molecules, causing inhibitory neurons to behave more like excitatory neurons,” Hong explains.
The researchers noted that the high prevalence of CP-AMPA receptors in PV neurons is consistent among various mammalian species, including humans.
“Reducing the specificity of neuron inhibition enhances the efficiency of our neural circuits compared to species lacking this molecular trait,” says Hong. “This likely also contributes to the stability of our neural networks.”
Hong mentions that this new research could also have ramifications in the realm of machine learning related to artificial intelligence.
“In machine learning, many computational ‘artificial’ neurons are fine-tuned to be very specific or less so,” he elaborates. “We aim to understand how these specific and less specific components can collaborate to develop smarter machines and more intelligent AI.”
Going forward, the scientists plan to take a closer look at additional crucial molecules that have an impact on cognition. Hong mentions that a deeper understanding of brain molecules that affect biased neuronal calculations could significantly advance the search for drug therapy targets in psychiatric disorders with genetic links, a promising area he terms ‘neurocomputational therapeutics.’
The research included contributions from various scientists: Juhyun Kim, Dong Won Kim, Richard C. Johnson, Nathachit Limjunyawong, Zhuonan Yang, David Cheon, Taeyoung Hwang, Amit Agarwal, Xinzhong Dong, Seth Blackshaw, Dwight E. Bergles, and Solange P. Brown from Johns Hopkins; Thomas Hainmueller, Thibault Cholvin, and Marlene Bartos from the University of Freiburg; Joram Keijser and Henning Sprekeler from the Technical University of Berlin; Soo Hyun Park and David A. Leopold from the National Institute of Mental Health; Fenna M. Krienen from Princeton University; and Steven A. McCarroll from Harvard Medical School.
This research was funded by grants from the National Institutes of Health (R37NS036715 and U01DA056556).
