Nav: Home

In Rett syndrome model, team shows how adult learning is impaired in females

January 18, 2017

Cold Spring Harbor, NY - Neurodevelopmental disorders like autism very likely have their origin at the dawn of life, with the emergence of inappropriate connectivity between nerve cells in the brain. In one such disorder, Rett syndrome, the pathology is traceable to the failure of a specific gene, called MECP2. Today, a team at Cold Spring Harbor Laboratory (CSHL) publishes results of experiments in mice suggesting how MECP2 mutations further impair affected individuals later on in life.

In mouse models of Rett syndrome - which in humans is seen overwhelmingly in females - the researchers have demonstrated how failure of Mecp2, the mouse equivalent of the human gene of the same name, has biological consequences that prevent adult females from learning how to gather newborn pups in the days immediately following the pups' birth.

"Pup-gathering behavior is a well-studied behavior in rodents, and an excellent way of testing the impact of Mecp2 mutations on the brain in females of child-bearing age," explains CSHL Associate Professor Stephen Shea, who led the research team.

"Although many people with Rett syndrome have severe handicaps from early in life, they frequently live well into adulthood," notes Keerthi Krishnan, Ph.D., now at University of Tennessee at Knoxville, who, with Billy Lau, Ph.D., performed much of the work as postdoctoral investigators at CSHL. "This is the first study in Rett syndrome we're aware of that explores how brain functions related to an experience-based natural behavior affect the adult female brain," Krishnan says.

The team discovered that during the five days following the birth of pups, normal Mecp2 gene expression is required in order for adult females to learn how to gather wayward pups into a nest. Videos shown here compare the learned pup-retrieval behavior in healthy adult females with the inability of females with impaired Mecp2 expression to learn the task when placed in the same cage as a healthy mom.

This inability to learn was traced by the team to a cascade of failures at the molecular level. These problems begin when both affected and unaffected females increase production of an enzyme called GAD67. The enzyme, in turn, spurs synthesis of the neurotransmitter GABA. These events apparently caused normal neural plasticity to go haywire in affected females. Central to this deficit were so-called PV+ neurons that release GABA in the auditory cortex. In mice with Mecp2 mutations, these neurons expressed elevated levels of parvalbumin (PV), a signaling protein.

When presented with the challenge of gathering newborn pups, adult female mice expressing a mutated and non-functional Mecp2 gene were unable to learn the behavior, which is normally triggered by the pups' high-pitched squeals. The neural network in the auditory cortex -- which processes the sounds -- is literally handcuffed. These same neurons also deployed structures called perineuronal nets (PNNs). PNNs are cage-like structures that assemble in the space surrounding individual PV+ neurons, likely restricting their ability to extend threadlike dendrites, or branches, to form synapses with other neurons. In healthy individuals, the transient forging of synapses lies at the heart of experience-based learning.

The work suggests there is a critical window of heightened sensitivity to cues from the senses - in this case, sounds made by newborn pups - during which neurons in adult females must be able to connect with others in order to learn a key behavior. Such plasticity is what the team found to be specifically inhibited in adult females by the train of events initiated by the PV+ neuronal network when Mecp2 was defective.

"This window of vulnerability reveals a role of Mecp2 mutations in facilitating adult plasticity, and this is distinct from the impact of these mutations on early development of the same individuals," Krishnan points out.

Using genetic and pharmacological interventions, the team was able to manipulate GABA in neural networks in the auditory cortex, restoring the ability of adult female mice to learn how to retrieve pups in the critical five-day window following the birth of pups. Shea suggests this restoration reflects the ability of neurons in the auditory cortex to correctly perceive the vocalizations of pups, something the adult mice modeling Rett syndrome are unable to do.

The lab's work on plasticity and learning is continuing, as is its exploration of the various ways in which Mecp2 mutations are expressed in different individuals. In males, with only one copy of Mecp2 owing to its location on the X chromosome, a severe mutation in the gene is often fatal. Females with Rett syndrome, having two X chromosomes and thus two copies of Mecp2, typically have problems with only one of those copies. Whether their "good" or "bad" copy of the gene is expressed in any given cell at any given moment is a random phenomenon, helping to explain the wide range of impacts Mecp2 mutations can have in different female individuals.
-end-
The research described here was supported by Simons Foundation Autism Research Initiative (SFARI), National Institute of Mental Health, Brain and Behavior Research Foundation and International Rett Syndrome Foundation.

"MECP2 regulates cortical plasticity underlying a learned behavior in adult female mice" appears January 18, 2017 in Nature Communications. The authors are: Keerthi Krishnan, Billy Y. B. Lau, Gabrielle Ewall, Z. Josh Huang and Stephen D. Shea. The paper can be accessed at: http://www.nature.com/ncomms/

About Cold Spring Harbor Laboratory

Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,100 people including 600 scientists, students and technicians. The Meetings & Courses Program hosts more than 12,000 scientists from around the world each year on its campuses in Long Island and in Suzhou, China. The Laboratory's education arm also includes an academic publishing house, a graduate school and programs for middle and high school students and teachers. For more information, visit http://www.cshl.edu

Cold Spring Harbor Laboratory

Related Neurons Articles:

New tool to identify and control neurons
One of the big challenges in the Neuroscience field is to understand how connections and communications trigger our behavior.
Neurons that regenerate, neurons that die
In a new study published in Neuron, investigators report on a transcription factor that they have found that can help certain neurons regenerate, while simultaneously killing others.
How neurons use crowdsourcing to make decisions
When many individual neurons collect data, how do they reach a unanimous decision?
Neurons can learn temporal patterns
Individual neurons can learn not only single responses to a particular signal, but also a series of reactions at precisely timed intervals.
A turbo engine for tracing neurons
Putting a turbo engine into an old car gives it an entirely new life -- suddenly it can go further, faster.
Brain neurons help keep track of time
Turning the theory of how the human brain perceives time on its head, a novel analysis in mice reveals that dopamine neuron activity plays a key role in judgment of time, slowing down the internal clock.
During infancy, neurons are still finding their places
Researchers have identified a large population of previously unrecognized young neurons that migrate in the human brain during the first few months of life, contributing to the expansion of the frontal lobe, a region important for social behavior and executive function.
How many types of neurons are there in the brain?
For decades, scientists have struggled to develop a comprehensive census of cell types in the brain.
Molecular body guards for neurons
In the brain, patterns of neural activity are perfectly balanced.
Engineering researchers use laser to 'weld' neurons
University of Alberta researchers have developed a method of connecting neurons, using ultrashort laser pulses -- a breakthrough technique that opens the door to new medical research and treatment opportunities.

Related Neurons Reading:

The Neuron: Cell and Molecular Biology
by Irwin B. Levitan (Author), Leonard K. Kaczmarek (Author)

The Neuron: Cell and Molecular Biology
by Irwin B. Levitan (Author), Leonard K. Kaczmarek (Author)

Mirror Neurons Will Save Your Life: How To Stop Being Controlled By Other People

From Neuron to Brain (5th Ed)
by John G. Nicholls (Author), A. Robert Martin (Author), David A. Brown (Author), Mathew E. Diamond (Author), David A. Weisblat (Author), Paul A. Fuchs (Author)

From Neurons to Neighborhoods : The Science of Early Childhood Development
by Committee on Integrating the Science of Early Childhood Development (Author), Youth, and Families Board on Children (Author), National Research Council (Author), Committee on Integrating the Science of Early Childhood Development (Author), Jack P. Shonkoff (Editor), Deborah A. Phillips (Editor)

From Photon to Neuron: Light, Imaging, Vision
by Philip Nelson (Author)

The Myth of Mirror Neurons: The Real Neuroscience of Communication and Cognition
by Gregory Hickok (Author)

The 7 Secrets of Neuron Leadership: What Top Military Commanders, Neuroscientists, and the Ancient Greeks Teach Us about Inspiring Teams
by Audible Studios

From Neurons to Neighborhoods: An Update: Workshop Summary (BCYF 25th Anniversary)
by National Research Council (Author), Division of Behavioral and Social Sciences and Education (Author), Institute of Medicine (Author), Youth, and Families Board on Children (Author), Steve Olson (Editor)

I of the Vortex: From Neurons to Self
by Rodolfo R. Llinas (Author)

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Bias And Perception
How does bias distort our thinking, our listening, our beliefs... and even our search results? How can we fight it? This hour, TED speakers explore ideas about the unconscious biases that shape us. Guests include writer and broadcaster Yassmin Abdel-Magied, climatologist J. Marshall Shepherd, journalist Andreas Ekström, and experimental psychologist Tony Salvador.
Now Playing: Science for the People

#514 Arctic Energy (Rebroadcast)
This week we're looking at how alternative energy works in the arctic. We speak to Louie Azzolini and Linda Todd from the Arctic Energy Alliance, a non-profit helping communities reduce their energy usage and transition to more affordable and sustainable forms of energy. And the lessons they're learning along the way can help those of us further south.