Study reveals reciprocal activity of brain proteins necessary for learning and memory

October 13, 2017

A UCLA team reports that a protein called IDOL targets and prevents overproduction of the synaptic protein ApoER2, an adjustment that allows connections between neurons to change during the learning process for humans and animals. The researchers conclude that reciprocal IDOL/ApoER2 activity in the brain allows synapses to undergo formation and disassembly as learning occurs.

Humans (and mice) learn by trial and error, a process that neuroscientists can explain on a cellular level. As learning proceeds, contact points called "synapses" between in a circuit strengthen during successful "trials," while non-productive circuits gradually weaken and fade away. The ability to reorganize pathways like this in the brain depends in part on cell shape. Stable synapses form when a neuron extends parts called "dendrites," which often have spines that serve as landing platforms for incoming nerve fibers. By contrast, synapses weaken as dendrites shrink or spines decrease in number or size. Strong synaptic connections also display a membrane called ApoER2; investigators reasoned that elimination of useless synapses might require removal of ApoER2. Working in animal models of Alzheimer's disease, this research group previously reported that IDOL triggered degradation of the LDL receptor, a protein that is highly similar to ApoER2.

The team confirmed that IDOL, whose normal job is to trigger destruction of unnecessary proteins, resides at in normal mouse brains. The researchers then upset the normal balance between IDOL and ApoER2 in a number of experimental contexts, including cultured neurons, mouse brain tissue slices, and living mice. Overall, they found that an abundance of ApoER2 in neurons was inversely related to IDOL activity. Experimental boosting of IDOL protein levels triggered ApoER2 loss in , as predicted, and impaired the formation of spines on dendrites. By contrast, experimental IDOL depletion in neurons cultured from the hippocampus, a primary site of memory storage in the brain, provoked unusually high ApoER2 expression, shrank dendritic spines, and blocked increases in synapse strength typically seen after intense electrical stimulation, a phenomenon called LTP (or long-term potentiation). Finally, mice engineered to lack the IDOL protein performed poorly in behavioral tests of spatial memory and fear-based conditioning. This work shows that IDOL protects neurons from producing too much ApoER2 protein and "locking in" to a cellular size, shape and structure incompatible with learning.

The paper reveals the IDOL/ApoER2 pair as key players governing cellular changes necessary for learning and memory, a highly researched topic in biology. Concurrently, the lab, which has up to now focused on lipid metabolism, has studied a different role played by IDOL in regulating levels of LDL, or "bad," cholesterol. The convergence of two different fields on IDOL raises the possibility that abnormal is linked to cognitive disorders, such as Alzheimer's disease, for which high cholesterol is a risk factor.

This study was published in the open-access, peer-reviewed journal eLife.

Explore further: Brain development and plasticity share similar signalling pathways

More information: Jie Gao et al. The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning, eLife (2017). DOI: 10.7554/eLife.29178

Related Stories

Brain development and plasticity share similar signalling pathways

October 10, 2017
October 2017. Learning and memory are two important functions of the brain that are based on the brain's plasticity. Scientists from Goethe University Frankfurt report in the latest issue of the scientific journal Cell Reports ...

A new view for protein turnover in the brain

August 7, 2017
Keeping the human brain in a healthy state requires a delicate balance between the generation of new cellular material and the destruction of old. Specialized structures known as lysosomes, found in nearly every cell in your ...

Mice offer a window into sleep's role in memory

March 24, 2017
Sleep provides essential support for learning and memory, but scientists do not fully understand how that process works on a molecular level. What happens to synapses, the connections between neurons, during sleep that helps ...

'Recycling protein' shown to affect learning and memory in mice

March 10, 2017
Learning and memory depend on cells' ability to strengthen and weaken circuits in the brain. Now, researchers at Johns Hopkins Medicine report that a protein involved in recycling other cell proteins plays an important role ...

Study implicates glial cells in fragile X syndrome

October 4, 2016
Research on fragile X syndrome, the most common inherited cause of mental retardation, has focused mostly on how the genetic defect alters the functioning of neurons in the brain. A new study focusing on a different type ...

Recommended for you

A little myelin goes a long way to restore nervous system function

October 24, 2017
In the central nervous system of humans and all other mammals, a vital insulating sheath composed of lipids and proteins around nerve fibers helps speed the electrical signals or nerve impulses that direct our bodies to walk, ...

Running on autopilot: Scientists find important new role for 'daydreaming' network

October 23, 2017
A brain network previously associated with daydreaming has been found to play an important role in allowing us to perform tasks on autopilot. Scientists at the University of Cambridge showed that far from being just 'background ...

Rhythm of memory: Inhibited neurons set the tempo for memory processes

October 23, 2017
The more we know about the billions of nerve cells in the brain, the less their interaction appears spontaneous and random. The harmony underlying the processing of memory contents has been revealed by Prof. Dr. Marlene Bartos' ...

Researchers demonstrate 'mind-reading' brain-decoding tech

October 23, 2017
Researchers have demonstrated how to decode what the human brain is seeing by using artificial intelligence to interpret fMRI scans from people watching videos, representing a sort of mind-reading technology.

Research revises our knowledge of how the brain learns to fear

October 23, 2017
Our brains wire themselves up during development according to a series of remarkable genetic programs that have evolved over millions of years. But so much of our behavior is the product of things we learn only after we emerge ...

Scientists use supercomputer to search for "memory molecules"

October 23, 2017
Until now, searching for genes related to memory capacity has been comparable to seeking out the proverbial "needle in a haystack." Scientists at the University of Basel made use of the CSCS supercomputer Piz Daint to discover ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.