News Article | 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. 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. "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. 1. The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 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.
Cromer J.R.,University of Connecticut |
Cromer J.A.,The Picower Institute for Learning and Memory |
Cromer J.A.,Massachusetts Institute of Technology |
Maruff P.,CogState Ltd |
And 2 more authors.
Experimental and Clinical Psychopharmacology | Year: 2010
Several psychological constructs (e.g., subjective perception of intoxication, visuomotor speed) display acute tolerance to alcohol, that is, show improvement at declining blood alcohol concentrations (BACs) relative to equivalent rising BACs. However, methodological challenges emerge when attempting to make such comparisons across limbs of the BAC curve, which have proven a barrier to advancing research on acute tolerance. To date, no studies have made multiple comparisons across the entire BAC trajectory. This study employs experimental procedures that overcome some of these difficulties, offering a clearer picture of recovery of impairment for subjective perception of intoxication and cognitive performance and the relationship between them. Twenty participants were assessed at multiple time points over 2 days. Continuous subjective perception of intoxication ratings and cognitive data derived from a computerized measure were paired with a novel analytic paradigm, which allowed comparisons at identified BACs. Results showed acute tolerance for individuals' subjective perception of intoxication and for performance on cognitive tasks measuring visuomotor speed and learning efficiency (recovery from impairment). In contrast, performance on measures of executive function and short-term memory showed no significant difference between limbs at exact concentrations (no recovery from impairment). Therefore, despite participants feeling less intoxicated over time, many cognitive functions remained impaired. The implication for these findings in terms of drunken driving behavior are substantial, suggesting that people may be likely to drive once they subjectively perceive that they have recovered from the acute intoxicating effects of alcohol, despite the persistence of " higher order" cognitive impairments. © 2010 American Psychological Association.
Fujino T.,The Picower Institute for Learning and Memory |
Leslie J.H.,The Picower Institute for Learning and Memory |
Eavri R.,The Picower Institute for Learning and Memory |
Chen J.L.,The Picower Institute for Learning and Memory |
And 9 more authors.
Genes and Development | Year: 2011
Use-dependent selection of optimal connections is a key feature of neural circuit development and, in the mature brain, underlies functional adaptation, such as is required for learning and memory. Activity patterns guide circuit refinement through selective stabilization or elimination of specific neuronal branches and synapses. The molecular signals that mediate activity-dependent synapse and arbor stabilization and maintenance remain elusive. We report that knockout of the activity-regulated gene cpg15 in mice delays developmental maturation of axonal and dendritic arbors visualized by anterograde tracing and diolistic labeling, respectively. Electrophysiology shows that synaptic maturation is also delayed, and electron microscopy confirms that many dendritic spines initially lack functional synaptic contacts. While circuits eventually develop, in vivo imaging reveals that spine maintenance is compromised in the adult, leading to a gradual attrition in spine numbers. Loss of cpg15 also results in poor learning. cpg15 knockout mice require more trails to learn, but once they learn, memories are retained. Our findings suggest that CPG15 acts to stabilize active synapses on dendritic spines, resulting in selective spine and arbor stabilization and synaptic maturation, and that synapse stabilization mediated by CPG15 is critical for efficient learning. © 2011 by Cold Spring Harbor Laboratory Press.
Hogg M.C.,Royal College of Surgeons in Ireland |
Mitchem M.R.,Royal College of Surgeons in Ireland |
Mitchem M.R.,The Picower Institute for Learning and Memory |
Konig H.-G.,Royal College of Surgeons in Ireland |
Prehn J.H.M.,Royal College of Surgeons in Ireland
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2016
In amyotrophic lateral sclerosis (ALS), it has been suggested that the process of neurodegeneration starts at the neuromuscular junction and is propagated back along axons towards motor neurons. Caspase-dependent pathways are well established as a cause of motor neuron death, and recent work in other disease models indicated a role for caspase 6 in axonal degeneration. Therefore we hypothesised that caspase 6 may be involved in motor neuron death in ALS. To investigate the role of caspase 6 in ALS we profiled protein levels of caspase-6 throughout disease progression in the ALS mouse model SOD1G93A; this did not reveal differences in caspase 6 levels during disease. To investigate the role of caspase 6 further we generated a colony with SOD1G93A transgenic mice lacking caspase 6. Analysis of the transgenic SOD1G93A; Casp6-/- revealed an exacerbated phenotype with motor dysfunction occurring earlier and a significantly shortened lifespan when compared to transgenic SOD1G93A; Casp6+/+ mice. Immunofluorescence analysis of the neuromuscular junction revealed no obvious difference between caspase 6+/+ and caspase 6-/- in non-transgenic mice, while the SOD1G93A transgenic mice showed severe degeneration compared to non-transgenic mice in both genotypes. Our data indicate that caspase-6 does not exacerbate ALS pathogenesis, but may have a protective role. © 2016 Elsevier B.V.
Melom J.E.,Massachusetts Institute of Technology |
Littleton J.T.,Massachusetts Institute of Technology |
Littleton J.T.,The Picower Institute for Learning and Memory
Current Opinion in Genetics and Development | Year: 2011
Recent insights into the genetic basis of neurological disease have led to the hypothesis that molecular pathways involved in synaptic growth, development, and stability are perturbed in a variety of mental disorders. Formation of a functional synapse is a complex process requiring stabilization of initial synaptic contacts by adhesive protein interactions, organization of presynaptic and postsynaptic specializations by scaffolding proteins, regulation of growth by intercellular signaling pathways, reorganization of the actin cytoskeleton, and proper endosomal trafficking of synaptic growth signaling complexes. Many neuropsychiatric disorders, including autism, schizophrenia, and intellectual disability, have been linked to inherited mutations which perturb these processes. Our understanding of the basic biology of synaptogenesis is therefore critical to unraveling the pathogenesis of neuropsychiatric disorders. © 2011 Elsevier Ltd.
PubMed | Whitehead Institute For Biomedical Research, Austrian Academy of Sciences, The Picower Institute for Learning and Memory and Massachusetts Institute of Technology
Type: | Journal: Cell stem cell | Year: 2017
An expansion of the cerebral neocortex is thought to be the foundation for the unique intellectual abilities of humans. It has been suggested that an increase in the proliferative potential of neural progenitors (NPs) underlies the expansion of the cortex and itsconvoluted appearance. Here we show that increasing NP proliferation induces expansion and folding in an invitro model of human corticogenesis. Deletion of PTEN stimulates proliferation and generates significantly larger and substantially folded cerebral organoids. This genetic modification allows sustained cell cycle re-entry, expansion of the progenitor population, and delayed neuronal differentiation, all key features of the developing human cortex. In contrast, Pten deletion in mouse organoids does not lead to folding. Finally, we utilized the expanded cerebral organoids to show that infection with Zika virus impairs cortical growth and folding. Our study provides new insights into the mechanisms regulating the structure and organization of the human cortex.
PubMed | The Picower Institute for Learning and Memory and Massachusetts Institute of Technology
Type: | Journal: Human molecular genetics | Year: 2016
Huntington disease-like 2 (HDL2) and Huntington disease (HD) are adult-onset neurodegenerative diseases characterized by movement disorders, psychiatric disturbances and cognitive decline. Brain tissue from HD and HDL2 patients shows degeneration of the striatum and ubiquitinated inclusions immunoreactive for polyglutamine (polyQ) antibodies. Despite these similarities, the diseases result from different genetic mutations. HD is caused by a CAG repeat expansion in the huntingtin (HTT) gene, while HDL2 results from an expansion at the junctophilin 3 (JPH3) locus. Recent evidence indicates that the HDL2 expansion may give rise to a toxic polyQ protein translated from an antisense mRNA derived from the JPH3 locus. To investigate this hypothesis, we generated and characterized a Drosophila HDL2 model and compared it with a previously established HD model. We find that neuronal expression of HDL2-Q15 is not toxic, while the expression of an expanded HDL2-Q138 protein is lethal. HDL2-Q138 forms large nuclear aggregates, with only smaller puncta observed in the cytoplasm. This is in contrast to what is observed in a Drosophila model of HD, where polyQ aggregates localize exclusively to the cytoplasm. Altering localization of HLD2 with the addition of a nuclear localization or nuclear export sequence demonstrates that nuclear accumulation is required for toxicity in the Drosophila HDL2 model. Directing HDL2-Q138 to the nucleus exacerbates toxicity in multiple tissue types, while confining HDL2-Q138 to the cytoplasm restores viability to control levels. We conclude that while HD and HDL2 have similar clinical profiles, distinct pathogenic mechanisms are likely to drive toxicity in Drosophila models of these disorders.
Krench M.,The Picower Institute for Learning and Memory |
Littleton J.T.,The Picower Institute for Learning and Memory
Fly | Year: 2013
Huntington disease (HD) is an inherited neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the huntingtin (Htt) gene. Despite years of research, there is no treatment that extends life for patients with the disorder. Similarly, little is known about which cellular pathways that are altered by pathogenic Huntingtin (Htt) protein expression are correlated with neuronal loss. As part of a longstanding effort to gain insights into HD pathology, we have been studying the protein in the context of the fruitfly Drosophila melanogaster. We generated transgenic HD models in Drosophila by engineering flies that carry a 12-exon fragment of the human Htt gene with or without the toxic trinucleotide repeat expansion. We also created variants with a monomeric red fluorescent protein (mRFP) tag fused to Htt that allows in vivo imaging of Htt protein localization and aggregation. While wild-type Htt remains diffuse throughout the cytoplasm of cells, pathogenic Htt forms insoluble aggregates that accumulate in neuronal soma and axons. Aggregates can physically block transport of numerous organelles along the axon. We have also observed that aggregates are formed quickly, within just a few hours of mutant Htt expression. To explore mechanisms of neurodegeneration in our HD model, we performed in vivo and in vitro screens to search for modifiers of viability and pathogenic Htt aggregation. Our results identified several novel candidates for HD therapeutics that can now be tested in mammalian models of HD. Furthermore, these experiments have highlighted the complex relationship between aggregates and toxicity that exists in HD.