Nav: Home

Rett Syndrome study finds mechanisms underlying its visual deficits

October 31, 2016

CAMBRIDGE, Mass. (October 31, 2016) - In research published this week in the Proceedings of the National Academy of Sciences (PNAS), researchers at the Whitehead Institute for Biomedical Research and the Picower Institute for Learning and Memory at Massachusetts Institute of Technology (MIT) have used precise genetic tools and sophisticated high-resolution electrophysiological measurements to track neurophysiological deficits resulting from the genetic mutation associated with Rett Syndrome (RTT). Further, they demonstrated the ability of recombinant human Insulin Like Growth Factor 1 (rhIGF1) and bumetanide to reverse such deficits in cell-type specific manner in RTT mice -- and provided further mechanistic basis for observed clinical benefits of using rhIGF1 to treat RTT patients.

Understanding the physiological alterations in intact brain circuits in neurodevelopmental disorders is a fundamental challenge for neuroscience. It has been known that RTT arises from loss-of-function mutations in the gene Mecp2 in the brain. But MeCP2 protein is ubiquitously expressed in many cell-types and sub-regions of the brain; hence its role in cell-specific brain circuits has remained a mystery. "When we try to understand the mechanisms by which the social brain is constructed, we start with a bottom-up view. Waves of gene expression (nature) and sequences of patterned network activity (nurture) interact to mold development of specific circuits in the brain. The interplay of these factors goes awry in neurodevelopmental disorders" says the paper's first lead author Abhishek Banerjee, who conducted the research while serving as a Simons Fellow and post-doctoral researcher at MIT's Picower Institute for Learning and Memory, and now a Marie Curie Fellow and a NARSAD Young Investigator.

The authors in this study wanted to better understand how Mecp2 mutations affect specific neuronal subtypes that cumulatively result in RTT. To that end, they conducted technically challenging whole-cell recording of synaptic responses in vivo in the visual cortex of MeCP2-mutant mice, as well as recording dynamic neuronal population activity using two-photon microscopy. "This approach allowed us to conduct a series of in vivo studies in MeCP2-knockout mice, to see specific effects as they cascade, and to observe the relationship between neuronal subtypes and how they alter network dynamics," Banerjee says.

These recordings demonstrated that MeCP2 mutation affects cortical pyramidal neurons by reducing their excitatory and inhibitory function, and increasing their excitatory/ inhibitory ratio (E/I). "Previously, researchers have used brain slices to study synaptic E/I balance and simple alterations in neural circuits. We extended these observations to study how synaptic E/I deficits actually affect circuit-level computations within intact cortical circuits--deficits that subtly alter neural processing in patients," Banerjee notes.

"The dual effect that Mecp2 mutation exerts on excitatory and inhibitory function causes imbalances that interfere with normal processing of information through the neuronal circuit; and the resulting abnormal signaling appears to cause the visual impairment found in RTT," observes Xin Tang, a study co-author and post-doctoral researcher at Whitehead Institute.

Following the resulting cascade of effects through the pyramidal neurons, the researchers also observed that the polarity of GABAergic inhibition was altered and that a specific form of inhibitory interneurons named parvalbumin-expressing (PV+) inhibitory interneurons had reduced responses. That GABA polarity and PV+ responses were ultimately affected by MeCP2 had previously not been recognized in an animal model of RTT.

Subsequently, the investigators treated MeCP2 mutant mice with rhIGF1, and found that it restored cortical population responses, GABA polarity, and normalized PV+ interneuronal responses. "Our previous work showed that rhIGF1 can benefit individual neurons affected by RTT. Now we've demonstrated that it can improve function for an entire circuit--and how it does so," explains senior author Mriganka Sur, the Paul E. and Lilah Newton Professor of Neuroscience, Director of the Simons Center for the Social Brain, and investigator in the Picower Institute for Learning and Memory at MIT.

"Initial clinical trials have already shown rhIGF1 has beneficial effects in treating RTT. This work helps to explain why there is therapeutic benefit, and lays the foundation for more targeted use of growth factors and other treatments," notes senior author Rudolf Jaenisch, Whitehead Institute Founding Member and professor of biology at MIT.
-end-
This work was supported by a postdoctoral fellowship from the Simons Center for the Social Brain, a predoctoral fellowship from HHMI, and grants from the NIH (R01EY007023, R01MH085802, HD 045022, and R37-CA084198) and the Simons Foundation.

Rudolf Jaenisch's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

Mriganka Sur is the Paul E. and Lilah Newton Professor of Neuroscience at Massachusetts Institute of Technology, where he directs the Simons Center for the Social Brain and is an investigator of the Picower Institute for Learning and Memory.

Abhishek Banerjee is currently the Marie Sk?odowska-Curie Fellow at the University of Zurich

Xin Tang is a post-doctoral researcher in the Jaenisch lab at Whitehead Institute.

Full Citation:

"Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett Syndrome"

Proceedings of the National Academy of Sciences, October 31, 2016.

Abhishek Banerjee (1,4*), Rajeev V. Rikhye (1*), Vincent Breton-Provencher (1), Xin Tang (2), Chenchen Li (3), Keji Li (1), Caroline A. Runyan (1), Zhanyan Fu (3), Rudolf Jaenisch (2†), and Mriganka Sur (1†)

1. The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, U.S.A.

2. The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, U.S.A

3. Broad Institute of MIT and Harvard, Cambridge, MA 02142, U.S.A.

† MIT, Cambridge, MA 02139, U.S.A.

Whitehead Institute is a world-renowned non-profit research institution dedicated to improving human health through basic biomedical research. Wholly independent in its governance, finances, and research programs, Whitehead shares a close affiliation with Massachusetts Institute of Technology through its faculty, who hold joint MIT appointments.

Whitehead Institute for Biomedical Research

Related Memory Articles:

Taking photos of experiences boosts visual memory, impairs auditory memory
A quick glance at any social media platform will tell you that people love taking photos of their experiences -- whether they're lying on the beach, touring a museum, or just waiting in line at the grocery store.
Think you know how to improve your memory? Think again
Research from Katherine Duncan at the University of Toronto suggests we may have to rethink how we improve memory.
Improving memory with magnets
The ability to remember sounds, and manipulate them in our minds, is incredibly important to our daily lives -- without it we would not be able to understand a sentence, or do simple arithmetic.
Who has the better memory -- men or women?
In the battle of the sexes, women have long claimed that they can remember things better and longer than men can.
New study of the memory through optogenetics
A collaboration between Universitat Autònoma de Barcelona and Harvard University pioneers the increase of memory using optogenetics in mice in Spain.
Peppermint tea can help improve your memory
Peppermint tea can improve long-term and working memory and in healthy adults.
A new glimpse into working memory
MIT study finds bursts of neural activity as the brain holds information in mind, overturns a long-held model.
Memory ensembles
For over forty years, neuro-scientists have been interested in the biological mechanisms underlying the storage of the information that our brain records every day.
What is your memory style?
Why is it that some people have richly detailed recollection of past experiences (episodic memory), while others tend to remember just the facts without details (semantic memory)?
Watching a memory form
Neuroscientists at Rosalind Franklin University of Medicine and Science have discovered a novel mechanism for memory formation.

Related Memory Reading:

Unlimited Memory: How to Use Advanced Learning Strategies to Learn Faster, Remember More and be More Productive
by Kevin Horsley (Author)

Memory Rescue: Supercharge Your Brain, Reverse Memory Loss, and Remember What Matters Most
by Daniel G. Amen (Author)

The Memory Book: The Classic Guide to Improving Your Memory at Work, at School, and at Play
by Harry Lorayne (Author), Jerry Lucas (Author)

Quantum Memory: Learn to Improve Your Memory with The World Memory Champion!
by Nightingale-Conant

Sea of Memories
by Lake Union Publishing

Memory Man (Memory Man series Book 1)
by Grand Central Publishing

Improving Memory: Understanding age-related memory loss
by M.D. Kirk R. Daffner (Author)

The Memory: A gripping psychological thriller with a heart-stopping twist
by Bookouture

Topical Memory System
by The Navigators (Producer)

Better Memory Now: Memory Training Tips to Creatively Learn Anything Quickly, Improve Memory, & Ability to Focus for Students, Professionals, & Everyone Else to Remember Anything, Increase Leadership
by AE Mind

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.