Creating memories involves more than seeing friends or taking pictures. The brain is constantly adapting to new information and stores memories by making connections between neurons called synapses. The way neurons do this – reaching arm-shaped dendrites to communicate with other neurons – requires a ballet of genes, signaling molecules, cell scaffolding, and protein-building machines.
A new study by scientists at Scripps Research and the Max Planck Florida Institute for Neuroscience finds a central role for a signaling molecule, a long, non-coding RNA that scientists have named ADEPTR.
Using a variety of technologies, including confocal and two-photon microscopy, they follow the movements of ADEPTR, observing its formation, displacement, clumping at the synapse, and activating other proteins when stimulated. ‘a neuron.
Its journey to the confines of a brain cell is made possible by a cell carrier tiptoeing along the microtubule scaffolding of a dendrite. Called motor kinesin, it deposits ADEPTR near the synapse junction, where it activates other proteins.
The team also found that if ADEPTR is silenced, new synapses do not form during stimulation.
The study “Synaptic targeting regulated by lncRNA ADEPTR activity mediates structural plasticity by localizing Sptn1 and AnkB in dendrites”, is published online April 16 in the journal Scientific advances.
Long non-coding RNAs have often been described as “genomic dark matter” because their role in cells has yet to be fully characterized, especially in neurons, says lead author of the study, the neuroscientist Scripps Research Sathyanarayanan Puthanveettil, PhD. The Puthanveettil team discovers that they play a signaling role in neural plasticity – how neurons adapt and change with experience.
“Here, we report the activity-dependent dendritic targeting of a newly transcribed non-coding long RNA to modulate synapse function, and describe its underlying mechanisms,” explains Puthanveettil. “These studies provide new insight into the functions of long non-coding RNAs at the synapse level.”
The first author is Eddie Grinman, a graduate student of the Puthanveettil lab.
Long non-coding RNA is a type of RNA that exceeds 200 nucleotides and does not translate into protein. There are thousands of these long non-coding RNAs in our cells, but in most cases their function is not yet known. What we do know is that in general they tend to stay in the cell nucleus. Some regulate the transcription of genes.
“It was surprising to see a long, non-coding RNA move from the nucleus to the synapse so quickly and with such robustness,” says Grinman.
The hippocampus is the part of the brain where learning, memory and emotions reside. By working on neurons in the mouse hippocampus, the team stimulated the neurons with pharmacological activators of learning-related signaling. They discovered using high-resolution molecular imaging techniques that the long, non-coding RNA ADEPTR was rapidly expressed and transported to the outer arms of the cell. There, ADEPTR molecules interact with proteins that play a role in the structural organization of synapses, proteins called spectrin 1 and ankyrin B.
They found that ADEPTR became downregulated if exposed to an inhibitory neurotransmitter, GABA.
“These findings add another layer of complexity in the modulation and plasticity of synapses,” says Puthanveettil. “Synaptically localized long non-coding RNAs are important regulators of adaptive neuronal function.”
In the future, the team intends to continue to characterize how stimulation affects neural plasticity. In addition, the authors hope to learn more about the role of ADEPTR in vivo.
“It would be interesting to know what role ADEPTR plays in forming new memories in living organisms,” says Grinman.
The work reveals one of the most fundamental processes of learning and memory, adapting to changing information and circumstances.
“Neural plasticity is what allows us to learn, respond to stimuli, and create long-term memories,” says Puthanveettil. “There is still a lot to learn about the magnificent complexity of this fundamental biological process.”