[PDF] Activity Dependent Gabaa Receptor Synaptic Plasticity Is Lost In Fmr1ko Mice eBook

Author : Alexia Gene
Publisher :
Page : pages
File Size : 26,32 MB
Release : 2022
Category :
ISBN :

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"Fast inhibitory neurotransmission in the brain is predominately controlled by GABAA receptors (GABARs) which act to regulate neuronal excitability. Abnormal signaling and plasticity of GABAergic neurons have been implicated in many CNS diseases, most relevant is the neurodevelopmental disorder Fragile X Syndrome (FXS). In FXS, regulation of the brain's excitatory-inhibitory balance is extremely important, since one of the pivotal characteristics is an increase in neuronal excitability. Although it has been suggested that the neurophysiology of hyperexcitability is partly due to a GABAergic hypofunction, there is insufficient evidence to support this theory. Therefore, experiments were designed here to test the hypothesis that hyperexcitability in FXS is the result of defective GABAergic transmission. My experimental plan was divided into two primary objectives, first I compared GABAergic signaling and plasticity in the cerebellum of both wild-type (WT) and FXS mice (Fmr1KO mice). The strengthening of synaptic connectivity was assessed using activity-dependent stimulation of GABAergic synapses on molecular layer interneurons (MLIs) in the cerebellum to tease apart the GABAR subtypes that are involved. My data demonstrates that WT MLIs undergo [alpha]3-mediated inhibitory long-term potentiation (iLTP) that is reliant on nitric oxide (NO) and cyclic guanosine monophosphate (cGMP), which can be observed by an increase in synapse connectivity. Unexpectedly, MLIs are also subject to [alpha]1-mediated inhibitory long-term depression (iLTD) that is dependent on group 1 metabotropic glutamate receptors (Gp 1 mGluRs). In contrast, Fmr1KO mice completely lack [alpha]3- mediated iLTP and possess an enhanced iLTD for both [alpha]1 and [alpha]3 synapses. Thus, we used a combinational therapeutic strategy to block Gp1 mGluRs, while simultaneously activating the pathway implicated in GABAergic plasticity to successfully rescue the enhanced iLTD and restore iLTP in Fmr1KO mice. Overall, these findings provide a novel mechanism for understanding synaptic connectivity in FXS while also describing a combination of small molecule therapeutics to correct deficits in synaptic plasticity"--

Author : Kay E. Davies
Publisher : Oxford University Press, USA
Page : 150 pages
File Size : 48,93 MB
Release : 1989
Category : Language Arts & Disciplines
ISBN :

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This new book is an up-to-date review of the clinical, epidemiological, and cytogenetic aspects of the fragile X (Martin-Bell) syndrome--the most common genetic cause of mental retardation after Down syndrome. The book includes the latest research findings concerning diagnosis on the basis of the appearance of a fragile site in cultured lymphocytes. It assumes little prior knowledge of the subject, and provides a clearly written, easy-to-understand discussion previously unavailable in a single reference source. The book will be of special interest to molecular biologists, cytogeneticists, medical geneticists, and clinicians and other professionals working with the mentally handicapped.

Author : Craig M. Powell
Publisher : Oxford University Press, USA
Page : 421 pages
File Size : 10,67 MB
Release : 2013
Category : Family & Relationships
ISBN : 0199744319

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The science of autism has seen tremendous breakthroughs in the past few decades. A multitude of relatively rare mutations have been identified to explain around 15 % of autism cases with many of these genetic causes systematically examined in animal models. This marriage of human genetics and basic neurobiology has led to major advances in our understanding of how these genetic mutations alter brain function and help to better understand the human disease. These scientific approaches are leading to the identification of potential therapeutic targets for autism that can be tested in the very same genetic models and hopefully translated into novel, rational therapies. The Autisms: Molecules to Model Systems provides a roadmap to many of these genetic causes of autism and clarifies what is known at the molecular, cellular, and circuit levels. Focusing on tractable genetic findings in human autism and painstakingly dissecting the underlying neurobiology, the book explains, is the key to understanding the pathophysiology of autism and ultimately to identifying novel treatments.

Author : Per Andersen
Publisher : Oxford University Press
Page : 892 pages
File Size : 40,96 MB
Release : 2007
Category : Medical
ISBN : 9780195100273

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The hippocampus is one of a group of remarkable structures embedded within the brain's medial temporal lobe. Long known to be important for memory, it has been a prime focus of neuroscience research for many years. The Hippocampus Book promises to facilitate developments in the field in a major way by bringing together, for the first time, contributions by leading international scientists knowledgeable about hippocampal anatomy, physiology, and function. This authoritative volume offers the most comprehensive, up-to-date account of what the hippocampus does, how it does it, and what happens when things go wrong. At the same time, it illustrates how research focusing on this single brain structure has revealed principles of wider generality for the whole brain in relation to anatomical connectivity, synaptic plasticity, cognition and behavior, and computational algorithms. Well-organized in its presentation of both theory and experimental data, this peerless work vividly illustrates the astonishing progress that has been made in unraveling the workings of the brain. The Hippocampus Book is destined to take a central place on every neuroscientist's bookshelf.

Author : Detlev Boison
Publisher : Oxford University Press
Page : 657 pages
File Size : 16,15 MB
Release : 2016
Category : Medical
ISBN : 0199322295

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Homeostatic Control of Brain Function offers a broad view of brain health and diverse perspectives for potential treatments, targeting key areas such as mitochondria, the immune system, epigenetic changes, and regulatory molecules such as ions, neuropeptides, and neuromodulators. Loss of homeostasis becomes expressed as a diverse array of neurological disorders. Each disorder has multiple comorbidities - with some crossing over several conditions - and often disease-specific treatments remain elusive. When current pharmacological therapies result in ineffective and inadequate outcomes, therapies to restore and maintain homeostatic functions can help improve brain health, no matter the diagnosis. Employing homeostatic therapies may lead to future cures or treatments that address multiple comorbidities. In an age where brain diseases such as Alzheimer's or Parkinson's are ever present, the incorporation of homeostatic techniques could successfully promote better overall brain health. Key Features include · A focus on the homeostatic controls that significantly depend on the way one lives, eats, and drinks. · Highlights from emerging research in non-pharmaceutical therapies including botanical medications, meditation, diet, and exercise. · Incorporation of homeostatic therapies into existing basic and clinical research paradigms. · Extensive scientific basic and clinical research ranging from molecules to disorders. · Emerging practical information for improving homeostasis. · Examples of homeostatic therapies in preventing and delaying dysfunction. Both editors, Detlev Boison and Susan Masino, bring their unique expertise in homeostatic research to the overall scope of this work. This book is accessible to all with an interest in brain health; scientist, clinician, student, and lay reader alike.

Author : Rob Willemsen
Publisher : Academic Press
Page : 500 pages
File Size : 32,27 MB
Release : 2017-05-26
Category : Medical
ISBN : 0128045078

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Fragile X Syndrome: From Genetics to Targeted Treatment provides a structured overview of the molecular and clinical background of the disorder as well as treatment options. The book discusses the detailed molecular information on each of the pathways involved with sufficient details for all whose research touches this pathway. It provides a state-of-the-art update on all clinical aspects associated with this syndrome, including phenotype, diagnostics and epidemiology. It also includes an overview of the lessons learned from the preclinical research and pioneering trials on the fragile X syndrome for the investigators involved in clinical trials of neurodevelopmental disorders. This book is written for academic researchers, pharmaceutical investigators, and clinicians in the field who work on the disorder, and for researchers involved in clinical trials of the fragile X syndrome or related disorders. “This fascinating book, edited by Rob Willemsen and Frank Kooy, summarizes the current knowledge of the molecular aspects of fragile X syndrome (FXS), andthe potential for therapies resulting from this knowledge...Particularly interesting is a review “fragile X research from a parental perspective,” which summarizes the results of an international survey of the attitudes of families with FXS relatives towards research...This book is also an essential reference book for genetic counselors...The book provides counselors with the necessary biological background for proper explanations to the relatives of FXS patients. Many parents acquire a substantial knowledge of the conditions afflicting their children. The book will be helpful for both families and counselors to manage the expectations of families participating in clinical trials...In conclusion, this book is essential for everyone who is involved in the diagnosis and treatment of FXS patients.” - European Journal of Human Genetics (September 2018) Provides a comprehensive overview of the molecular genetics, clinical trials, and treatment of Fragile X Syndrome Written for academic researchers, pharmaceutical investigators, and clinicians in the field Edited by international leaders in the field who have contributed greatly to the study of Fragile X Syndrome Directs the reader through complex issues surrounding FXS and draws the literature together for researchers and clinicians

Author : Melanie A. Woodin
Publisher : Springer Science & Business Media
Page : 191 pages
File Size : 34,6 MB
Release : 2010-11-02
Category : Medical
ISBN : 1441969780

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This volume will explore the most recent findings on cellular mechanisms of inhibitory plasticity and its functional role in shaping neuronal circuits, their rewiring in response to experience, drug addiction and in neuropathology. Inhibitory Synaptic Plasticity will be of particular interest to neuroscientists and neurophysiologists.