Rosenmund Lab at Long Night of the Sciences

May 2011

Berlin’s summertime Long Night of the Sciences is always a big event for the local scientific community – all across the city research institutes and teaching facilities open their doors to the public. Passersby get a first-hand look at how science works, while scientists rise to the challenge of making their research understandable to the general public. This year, the Rosenmund lab joined in. Visitors, mainly youngsters, examined cells through a microscope and listened to Christian Rosenmund try his hand at a simple explanation of “why we move when we want to”.

Getting into the swing of things

The only way is up!May 2011

After a good year of settling into its new home of Berlin, the Rosenmund lab went on its first official lab retreat in May. As in science, the lab’s outing had to have a challenge – the destination was the tree-top adventure park in Wühlheide. Next year's retreat... Wildwater rafting anyone?


New paper decodes crucial component in brain signal processing

A new paper from our lab published in the current issue of Neuron presents surprising information about how the human brain processes electrical and chemical signals. In a collaboration between the Charité lab and our former lab at Baylor College of Medicine in Texas, we demonstrate a mechanism by which the brain regulates synaptic strength, with vesicular glutamate transporters (VGLUTs) and the protein endophilin playing a key role. The discovery goes a long way towards explaining the diversity of synaptic function.

The central nervous system processes a large variety of information, including sensory processing and motor control, body homeostasis, emotions, and higher cognitive functions, within hundreds of anatomically and functionally distinct circuits. To accomplish this diversity, the neurons and synapses underlying these circuits employ a large set of tools including variation in neuronal morphology, synaptic connectivity, electrical processing within the neuron, and synaptic function. Presynaptic release probabilities contribute significantly to the functional diversity of synapses. They determine both the initial reliability of a synaptic connection and the short-term plasticity characteristics, as low-release probability synapses show facilitation, while high-release probability synapses tend to depress during action potential trains. The molecular mechanisms for the diversity of release probability are practically unknown.

Our new paper demonstrates a molecular mechanism of regulation of release probability that contributes to the functional diversity of different synapse populations. We identify endophilin A1 as a positive regulator of release probability and show how differential expression of VGLUT isoforms in neurons interact with endophilin A1 to shape the synaptic response. We propose the following model for the VGLUT isoforms’ regulation of release probability (see figure). The model shows that endophilin dimerizes and binds to synaptic vesicle membranes to achieve an active state that enhances release efficiency. VGLUT2-containing vesicles (top left) have high levels of active endophilin and high-release probability, while VGLUT1-containing vesicles (top right) have lower levels of active endophilin because of the inhibitory actions of VGLUT1. Overexpression of endophilin (bottom left) overwhelms the available VGLUT1 molecules and raises the level of active endophilin and the probability of vesicle release. Knockdown of endophilin (bottom right) severely decreases levels of active endophilin and the probability of vesicle release.

The classical role of VGLUTs is to fill vesicles with glutamate, and therefore the additional role in regulating release probability is surprising. Although previous research had shown that the distribution of VGLUT1 and VGLUT2 overlaps with that of synapses with different reliability, it was difficult to imagine how a vesicular neurotransmitter transporter might cause synapses to release glutamatergic vesicles with different probability. Our research provided us with a molecular explanation for the correlation between VGLUT expression and release probability.

Previous studies have shown that VGLUT levels are endogenously and bidirectionally regulated during development, in disease states, with pharmacological manipulation, and according to circadian rhythms. Our data suggest these alterations would be accompanied by changes in neuronal firing patterns and perhaps circuit behavior. For example, differences between VGLUT1 and VGLUT2/3 could be important during development, where the early, transient expression of VGLUT2 and VGLUT3 in neurons that later express VGLUT1 could increase the chance of glutamate release at synapses that may contain fewer synaptic vesicles than mature synapses. It is possible that neurons or networks of neurons actively use specific VGLUT isoform expression to regulate the efficiency of glutamate release.

Our results also led us to speculate the mechanism by which endophilin promotes endocytosis and enhances release probability are one and the same and that it acts at the step of vesicle retrieval from the plasma membrane to form vesicles that have an intrinsically higher release probability. This could be accomplished by altering the curvature of synaptic vesicles, altering the timing of membrane scission, or altering the internalization of endocytic cargo.

We now plan to explain how the nervous system uses the different VGLUTs in more detail, and investigate the pathophysiological relevance of VGLUTs.

Weston et al., Interplay between VGLUT Isoforms and Endophilin A1 Regulates Neurotransmitter Release and Short-Term Plasticity, Neuron (2011), doi:10.1016/j.neuron.2011.02.002

Link to the abstract (including video):

Paper on the role of MeCP2 in Rett syndrome published in Nature

A new research paper, from the previous Rosenmund/Zoghbi lab at the Baylor College of Medicine in Houston, on the role of MeCP2 in Rett syndrome has been published in the current issue of Nature. Rett syndrome is a devastating neurological disorder caused by mutations in a gene called MeCP2. Children, mostly girls, born with Rett syndrome, appear normal at first, but stop or slow intellectual and motor development between three months and three years of age, losing speech, developing learning and gait problems. Some of their symptoms resemble those of autism.
Specifically, the paper shows that loss of the protein MeCP2 in a special group of inhibitory nerve cells in the brain reproduces nearly all Rett syndrome features. These inhibitory (gamma-amino-butyric-acid [GABA]-ergic) neurons make up only 15 to 20 percent of the total number of neurons in the brain. Loss of MeCP2 causes a 30 to 40 percent reduction in the amount of GABA, the specific signaling chemical made by these neurons. This loss impairs how these neurons communicate with other neurons in the brain. The inhibitory neurons keep the brakes on the communication system, enabling proper transfer of information.
"In effect, the lack of MeCP2 impairs the GABAergic neurons that are key regulators governing the transfer of information in the brain," said Dr. Hsiao-Tuan Chao, first author of the report.
Chao, whose PhD thesis was co-mentored by Professors Rosenmund and Zoghbi, made the discovery by developing a mouse model that allowed researchers to remove MeCP2 from only the GABAergic neurons.
"We did this study thinking that perhaps all we would see was a few symptoms of Rett syndrome," said Chao. "Strikingly, we saw that removing MeCP2 solely from GABAergic neurons reproduced almost all the features of Rett syndrome, including cognitive deficits, breathing difficulties, compulsive behavior, and repetitive stereotyped movements. The study tells us that MeCP2 is a key protein for the function of these neurons."
Once the authors determined that the key problem rested with the GABAergic neurons, they sought to find out how the lack of MeCP2 disturbed the function of these neurons. Chao discovered that losing MeCP2 caused the GABAergic neurons to release less of the neurotransmitter, GABA. This occurs because losing MeCP2 reduces the amount of the enzymes required for the production of GABA.
Intriguingly, prior studies showed that expression of these enzymes is also reduced in some patients with autism, schizophrenia and bipolar disorder, said Chao.
"This tells us a lot about what is going on in the brains of people with Rett syndrome, autism or even schizophrenia," said Chao. "A child is born healthy. She starts to grow and then begins to lose developmental milestones. Communication between neurons is impaired, in part due to reduced signals from GABAergic neurons."
Others who took part in this work include Hongmei Chen, Rodney C. Samaco, Mingshan Xue, Maria Chahrour, Jong Yoo, Jeffrey L. Neul, Hui-Chen Lu, Jeffrey L. Noebels and Huda Zoghbi, all of BCM, John L.R. Rubenstein of University of Calfornia in San Francisco, Marc Ekker of University of Ottawa in Ontario, and Shiaoching Gong and Nathaniel Heintz of The Rockefeller University in New York.
Funding for this work came from the Howard Hughes Medical Institute, the National Institute of Neurological Disorders and Stroke, the Simons Foundation, the Rett Syndrome Research Trust, the Intellectual and Developmental Disability Research Centers, the International Rett Syndrome Foundation, Autism Speaks, the National Institute of Mental Health, Baylor Research Advocates for Student Scientists and McNair Fellowships.


Adapted from BCM press release, dated 10/11/10.

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