Entity

Time filter

Source Type

Cambridge, MA, United States

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. Source


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. Source


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. Source


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. Source


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. Source

Discover hidden collaborations