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FMRP proteins perform distinct functions in the cell bodies (yellow) and dendrites (red) of hippocampal memory neurons
.
Source: Rockefeller University Molecular Neuro-Oncology Laboratory
What happens inside neurons when we remember passwords or learn the cello? Some of our fundamental understanding of learning and memory comes from studies of conditions that disrupt cognitive development
.
For example, FMRP, the deletion of a protein that causes Fragile X syndrome, intellectual disability and some forms of autism, has been shown to play a key role in these brain functions, helping to regulate the synaptic connections between neurons
Now a new study shows that the protein's role is more complex than previously known
.
By looking at memory neurons in the hippocampus of the mouse brain, the Rockefeller scientists discovered that FMRP has two distinct functions
"By microdissecting brain tissue, we were able to show that this protein controls different functions at different cellular locations," said Rockefeller University Professor Robert Darnell and HHMI Fellow, who led the study
.
The findings, published in the journal eLife, may shed new light on the underlying mechanisms of learning and memory, intellectual disability and autism
.
main regulator
The formation of each memory, or the disappearance of another, requires changes in the strength of synapses between neurons
.
When incoming signals reach neurons in the form of electrical signals, neurons can change the strength of synapses, for example by creating new receptors or removing old ones.
Production of this protein occurs on the cell's dendrites, which are filled with RNA molecules waiting to be translated into proteins
.
FMRP acts like a switch, delaying translation by binding to the RNA sequence, and then initiating translation by dissociating from the RNA
More than 900 RNAs are known to be directly bound and regulated by FMRP
.
To better understand the protein's role in learning and memory, Darnell and his colleagues used molecular genetics to label individual mouse neurons and then dissected synapses and cell bodies by hand to isolate them
The dendritic portion contains RNA-bound FMRP whose protein product can alter synaptic responses
.
Meanwhile, inside the cell body of the same neuron, the protein binds to a different RNA that encodes a chromatin modifier, a protein that regulates gene expression by entering the nucleus and adding chemical tags to DNA
.
The findings suggest that FMRP helps create a feedback loop between the nucleus and dendrites, a mechanism that Darnell believes may provide a communication between the cell's command center and thousands of distant stretches that enable Synaptic responses are under control
.
"If neurons are not tightly controlled, they can become increasingly excited, eventually leading to seizures, a phenomenon seen in Fragile X syndrome
.
The system is designed to control itself,
Magazine
eLife
DOI
10.
