Finding the way to memory: Guidance proteins regulate brain plasticity

February 4, 2013

Our ability to learn and form new memories is fully dependent on the brain's ability to be plastic – that is to change and adapt according to new experiences and environments. A new study from the Montreal Neurological Institute – The Neuro, McGill University, reveals that DCC, the receptor for a crucial protein in the nervous system known as netrin, plays a key role in regulating the plasticity of nerve cell connections in the brain. The absence of DCC leads to the type of memory loss experienced by Dr. Brenda Milner's famous subject HM. Although HM's memory loss resulted from the removal of an entire brain structure, this study shows that just removing DCC causes the same type of memory deficit. The finding published in this week's issue of Cell Reports, extends Dr. Milner's seminal finding to another level, revealing a key part of the molecular basis for learning and memory.

Although both netrin and DCC are essential for normal development (in terms of guiding nerve cell growth) until now their function in the was not known. Dr. Tim Kennedy, lead researcher and neuroscientist at The Neuro, contributed to the discovery of netrins as a young post-doctoral fellow. This new study reveals the answer to the question that drove him to first start a lab. "I remember that exact moment when I knew I could run a research lab, it was 1993 and I was studying the developing nervous system and I was amazed to spot netrins in the adult brain - raising the important question, 'what are they doing there?' 20 years of dedicated research later the answer provides an important piece of the puzzle for understanding our and neurological disorders.

"The power of this study is that it looks at the animal on all levels, molecular, structural, and behavioural. We show that the netrin receptor DCC is a critical component of synapses between neurons in the adult brain, and is required for synapses to function properly. To demonstrate this, we selectively removed DCC from a specific subset of neurons in the adult mouse brain. This results in progressive degeneration of synapses, leading to defects in synaptic plasticity and memory. The synapses continue to function in that they still communicate but, the synapses cannot adjust or change in response to . Therefore, you can't learn anymore."

Furthermore, DCC deletion from mature neurons results in changes in the shape of specialized protrusions called dendritic spines, and alters the NMDA receptor, a critical trigger for mechanisms that make changes in synaptic strength. Therefore the study reveals that DCC is required to maintain proper synapse morphology or shape, and to regulate the ability of the NMDA receptor to switch on, which ensures activity-dependent synaptic plasticity.

Mutant mice that entirely lack DCC in all cells do not survive past birth and exhibit major defects in brain development. In order to investigate the function of netrin in the adult brain, researchers from the Netherlands Cancer Institute, collaborators on this study, engineered a new strain of floxed mice, in which the DCC gene can be selectively deleted from a specific sub-set of cells. Floxing involves putting short sequences of DNA on either side of a gene sequence. An enzyme that is activated later in life then recombines the DNA and cuts out the intervening sequence – deleting the gene only from specific cells. The Kennedy lab activated this enzyme only in the mature mouse brain, and limited activation to only a subset of neurons, consequently deleting the DCC gene from only from these neurons. These mice live to adulthood (DCC is made normally in all other cells in the mouse) as the enzyme only turns on and deletes DCC in specific cells in the adult brain. Although the mice otherwise appear normal, testing their behavior revealed severe deficits in their ability to form certain types of new long-term memories.

This study provides important new insight into the neural mechanisms of , processes that are fundamental to our existence, survival, and everyday life.

Explore further: A gene that protects against colorectal cancers

More information: Paper: download.cell.com/cell-reports … df?intermediate=true

Related Stories

A gene that protects against colorectal cancers

December 14, 2011
The research team in France has developed an animal model carrying a mutation of the DCC gene. Mice carrying the mutation develop tumours, because this gene can no longer induce the death of the cancer cells. This discovery ...

Recommended for you

Faulty support cells disrupt communication in brains of people with schizophrenia

July 20, 2017
New research has identified the culprit behind the wiring problems in the brains of people with schizophrenia. When researchers transplanted human brain cells generated from individuals diagnosed with childhood-onset schizophrenia ...

Scientists discover combined sensory map for heat, humidity in fly brain

July 20, 2017
Northwestern University neuroscientists now can visualize how fruit flies sense and process humidity and temperature together through a "sensory map" within their brains, according to new research.

Scientists reveal how patterns of brain activity direct specific body movements

July 20, 2017
New research by Columbia scientists offers fresh insight into how the brain tells the body to move, from simple behaviors like walking, to trained movements that may take years to master. The discovery in mice advances knowledge ...

Team traces masculinization in mice to estrogen receptor in inhibitory neurons

July 20, 2017
Researchers at Cold Spring Harbor Laboratory (CSHL) have opened a black box in the brain whose contents explain one of the remarkable yet mysterious facts of life.

Speech language therapy delivered through the Internet leads to similar improvements as in-person treatment

July 20, 2017
Telerehabilitation helps healthcare professionals reach more patients in need, but some worry it doesn't offer the same quality of care as in-person treatment. This isn't the case, according to recent research by Baycrest.

New study reveals contrasts in how groups of neurons function during decision making

July 19, 2017
By training mice to perform a sound identification task in a virtual reality maze, researchers at Harvard Medical School and the Istituto Italiano di Tecnologia (IIT) have identified striking contrasts in how groups of neurons ...

0 comments

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.