Neuroscientists at Tufts University School of Medicine in collaboration with colleagues at Yale University School of Medicine have discovered a new molecular mechanism essential for the maturation of brain function and can be used to restore plasticity in aged brains. Unlike earlier research that has extensively manipulated brain plasticity using approaches that affected the entire brain, this study aims, for the first time, to specifically target a single molecule of neuronal connection to modulate brain function. This restores the brain's ability to reconnect.
Research into mice could advance the understanding and treatment of human diseases such as autism spectrum disorders and stroke. It is published in Cell Reports on January 8, 2019.
The human brain is very plastic during childhood, and all young mammals have a "critical period" when different areas of their brains can reshape neural connections in response to external stimuli. The breach of this precise sequence of development results in serious damage; Conditions such as autism potentially involve interrupted critical periods.
"It has been known for some time that the maturation of inhibitory nerve cells in the brain controls the onset of the plasticity of the critical period, but as that plasticity decreases as the brain matures, it is not understood," said Dr. Adma Ribic, Ph.D., researcher of the Tufts School of Medicine and first author of the new study. "We had some evidence that a set of molecules called SynCAMs may be involved in this process, so we decided to delve into those specific molecules."
The study focused on the visual cortex, the part of the brain responsible for processing visual scenes, in which plasticity was examined in many species. Using advanced viral tools and electrophysiological techniques, researchers were able to measure the activity of nerve cells (neurons) in awake rats responding freely to visual stimuli. They found that the removal of the SynCAM 1 molecule from the brain increased plasticity in the visual cortex of young and adult mice. Additional research has found that SynCAM 1 controls a very specific type of neuronal connection called synapses: the long-distance synapses between the visual thalamus located below the cerebral cortex and the inhibitory neurons in the cortex. SynCAM 1 has been shown to be necessary for the formation of synapses between thalamus and inhibitory neurons, which in turn helps inhibitory neurons to mature and actively restrict the plasticity of the critical period.
Ribic compares the inhibitory neurons to a dial-up control when brain plasticity can occur. Plasticity is needed during early development as the function of different areas of the brain matures. The mature function is then "cemented" in place by molecules such as SynCAM 1.
"Our study identified a fundamental mechanism that controls brain plasticity, and perhaps more exciting, we can show that a process in the adult brain actively suppresses plasticity," said study senior author Thomas Biederer, Ph.D., associate professor of neuroscience of Tufts. Faculty of Medicine and member of the neuroscience course at the Sackler Faculty of Post-Graduation in Biomedical Sciences at Tufts. "Therefore, the limited ability of the mature brain to change is not simply a consequence of age, but is directly imposed by the SynCAM 1 mechanism. This allows us to target the mechanism to reopen plasticity in the mature brain, which could be relevant to treatment of disorders such as autism. "
Concentrating on a single molecule and type of synapse to induce increased plasticity should support the development of treatments with reduced potential for side effects. "For example, antidepressants can restore plasticity, but they will also have many other effects," said Ribic, who noted that more plasticity is not always better. "Our study found a way to increase plasticity in a very controlled way, spatially and temporally. Combined with the latest approaches to genetic manipulation, this may prove to be a new way to combat both childhood disorders and brain injury in adults. "
Researchers have yet to determine whether this plasticity mechanism will work in both humans and mice and can be activated repeatedly. While there are obviously large differences between rodents and humans, studies in several species suggest that the general mechanisms of plasticity are similar.
The study is the latest work by the Biederer group at Tufts University School of Medicine, which focuses on mechanisms of synapse formation and plasticity in the context of normal development and neurodevelopmental disorders.
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