METABOTROPIC GLUTAMATE RECEPTORS
Kimberly M Huber
Neurosciencebrown University
164 Angell Street
providence, Ri 02912
Grant 1F32EY006885-01 from National Eye Institute IRG: ZRG1
Keywords: developmental neurobiology, direct cortical response, glutamate receptor, long term potentiation, neural plasticity, visual cortex eye pharmacology, inhibitor /antagonist, inositol phosphate electrophysiology, laboratory mouse, laboratory rat
1F32EY006885-01 (1997): $29600
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Kimberly M Huber
Mechanisms Of MGluR-dependent Synaptic Plasticity
Kimberly M Huber
University Of Texas Sw Med Ctr/dallas Dallas, Tx 753909105
Grant 5R01NS045711-04 from National Institute Of Neurological Disorders And Stroke IRG: MDCN
Abstract: The group 1 metabotropic, or G-protein coupled, glutamate receptors (mGluRs) induced long-term changes in neuronal function. Group 1 mGluRs, in particular, has been implicated in many behaviors which are a result of persistent alterations in brain neuronal circuitry, such as learning and memory, drug addiction, chronic pain, and cortical development. Recent work has demonstrated that mGluR activation induces persistent changes in neurons by a direct regulation of protein synthesis. For example, activation of group 1 mGluRs with the selective agonist, dihydroxyphenylglycine (DHPG), or synaptic stimulation, induces a robust and long-term depression (mGluR-LTD) of excitatory synaptic transmission in hippocampal area CA1 neurons. The synaptic mechanism that underlies LTD is thought to be the rapid internalization of the postsynaptic AMPA subtype of glutamate receptors, the receptors responsible for synaptic transmission at the CA1 synapse. Remarkably, the persistence of mGluR-LTD and AMPAR internalization is mediated by the rapid protein synthesis at hippocampal dendrites. Although the existence of dendritic polyribosomes has been known for sometime, virtually nothing is known about how synaptic protein synthesis is regulated by group 1 mGluRs, or how these new proteins alter synaptic function. Furthermore, there has been no functional role ascribed to mGluR dependent LTD in the forebrain. The main objective of this work is to determine the cellular mechanisms of mGluR-dependent regulation of synaptic strength and investigate possible functional roles for mGluR-LTD. Briefly, the specific aims of the proposed research are as follows 1 Investigate candidate cellular mechanisms in synaptically and pharmacologically induced mGluR-dependent synaptic plasticity. 2 Identify regulatory mechanisms of protein synthesis activated by mGluRs and test their functional role in mGluR-dependent synaptic plasticity. 3 Determine developmental changes in pre- and postsynaptic mechanisms of mGluR-LTD expression. 4 Evaluate the role of group 1mGluRs in synapse development and maturation.
Keywords: developmental neurobiology, genetic translation, glutamate receptor, neural plasticity, neuroregulation, receptor expression, synapse, G protein, dendrite, genetic regulation, hippocampus, neuroanatomy, ribosome, brain imaging /visualization /scanning, laboratory mouse, laboratory rat, sectioning
Project start date: 2003-09-30
Project end date: 2007-07-31
5R01NS045711-04 (2006): $317045
5R01NS045711-03 (2005): $324675
5R01NS045711-02 (2004): $324675
1R01NS045711-01A1 (2003): $324675
STUDY OF FRAGILE X MENTAL RETARDATION PROTEIN IN SYNAPTIC FUNCTION AND PLASTICITY
Kimberly M Huber
University Of Texas Sw Med Ctr/dallas, Dallas, Tx 75390-9105
Grant 3R01HD052731-02S1 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and is caused by loss of function mutations in the Fragile X Mental Retardation gene (FMR1). Patients with FXS as well as other forms of mental retardation have an excess of dendritic spines as well as longer spines, suggesting that abnormal postsynaptic function, development or plasticity contributes to the cognitive deficits of this disease. Fragile X Mental Retardation Protein (FMRP), the protein product of FMR1, is an RNA binding protein and is thought to regulate translation of proteins in dendrites and dendritic spines. Such local or synaptic protein synthesis regulates both synapse development and long-term plasticity in mature animals. Therefore, FMRP most likely mediates its neuronal effects through translational regulation of synaptic proteins. Consistent with this idea, we and others have discovered that FMRP regulates synapse pruning in adolescent neurons as well as long-term synaptic depression by metabotropic glutamate receptors (mGluRs). Exactly how FMRP regulates synapse development and plasticity is unknown. Whether these effects are due to translational regulation of dendritically synthesized proteins or the identity of such proteins is also unknown. Here we propose to examine the cellular mechanisms by which FMRP regulates synapse development and mGluR- dependent synaptic plasticity. We will also examine how FMRP regulates the synthesis of proteins in dendrites and test 2 candidate proteins for their role in FMRP mediated synaptic pruning and mGluR-induced synaptic depression. Developing and testing new therapeutic strategies for treatment of FXS and autism, such as mGluR antagonists, is a mission of the NIH. Our results are expected to provide knowledge of how FMRP, or its absence, regulates synapse maturation and mGluR-dependent synaptic plasticity in the adult. These results will help to determine the neurobiological basis of mental retardation and related disorders such as autism as well as test if mGluR antagonists are a suitable therapeutic strategy for FXS. The specific aims of the grant are 1. Examine FMRP regulation of synapse development and elimination. 2 Determine the role of FMRP phosphorylation in regulation of synapse number and mGluR-induced dendritic protein synthesis, 3. Determine if FMRP is an acute regulator of LTD, 4. Test candidate proteins for their involvement in LTD and FMRP induced synapse elimination.Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and a leading cause of autism. FXS is caused by loss of function mutations in the Fragile X Mental Retardation protein (FMRP). Our research will determine how FMRP normally works in the brain as well as how and why the brain functions differently without FMRP. This work is expected to provide important knowledge to development therapies for mental retardation and autism
Keywords: 21+ years old; Acute; Adolescent; Adolescent Youth; Adult; Affect; Alteplase; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Brain; Cognitive deficits; Data; Dendrites; Dendritic Spines; Dephosphorylation; Development; Disease; Disorder; Encephalon; Encephalons; Escalante syndrome; FMR-1 Protein; FMR1; FMR1 Gene; FMR1 Protein; FMR1 protein, fragile X; FMRP protein; Fmr1 gene, ; Fmr1, ; Fragile X; Fragile X Mental Retardation 1 Gene; Fragile X Mental Retardation Protein; Fragile X Syndrome; GRM1; Gene Products, RNA; Glutamate Receptor, Metabotropic 1; Grant; Hereditary; Human, Adult; Inherited; Kanner`s Syndrome; Knock-out; Knockout; Knockout Mice; Knowledge; Long-Term Depression (Neurophysiology); Long-Term Depression (Physiology); Long-Term Synaptic Depression; MGLUR1; Martin-Bell Syndrome; Martin-Bell-Renpenning syndrome; Mediating; Mental Retardation; Messenger RNA; Metabotropic Glutamate Receptors; Mice, Knock-out; Mice, Knockout; Mission; NIH; NRVS-SYS; National Institutes of Health; National Institutes of Health (U.S.); Nerve Cells; Nerve Unit; Nervous System; Nervous System, Brain; Nervous system structure; Neural Cell; Neural Transmission; Neurobiology; Neurocyte; Neurologic Body System; Neurologic Organ System; Neurons; Null Mouse; PLAT; PP2A; PP2A Subunit B Prime; PPP2R4; PR53; PTPA; Patients; Peptide Biosynthesis, Ribosomal; Phenotype; Phosphoprotein Phosphatase; Phosphoprotein Phosphatase-2C; Phosphoprotein Phosphohydrolase; Phosphorylation; Phosphotyrosyl Phosphatase Activator; Play; Polyribosomes; Polysomes; Property; Property, LOINC Axis 2; Protein Biosynthesis; Protein Biosynthesis, Ribosomal; Protein Dephosphorylation; Protein Phosphatase 2A Regulatory Subunit B Prime; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Phosphatase C; Protein Phosphatase-1; Protein Phosphatase-2A; Protein Phosphorylation; Protein Synthesis, Ribosomal; Protein phosphatase; Proteins; RNA; RNA, Messenger; RNA, Non-Polyadenylated; RNA-Binding Proteins; Receptors, Metabotropic Glutamate; Recombinant Tissue Plasminogen Activator; Regulation; Renpenning syndrome 2; Research; Ribonucleic Acid; Role; Spinal Column; Spine; Staging; Synapses; Synaptic; Synaptic Transmission; Synaptic plasticity; Syndrome; T-Plasminogen Activator; TTPA; Testing; Therapeutic; Tissue Activator D-44; Tissue Plasminogen Activator; Tissue-Type Plasminogen Activator; Translational Regulation; Translations; United States National Institutes of Health; Vertebral column; Work; X-linked mental deficiency-megalotestes syndrome; X-linked mental retardation with fragile X syndrome; X-linked mental retardation-fragile site 1 syndrome; adult animal; adult human (21+); autism-fragile X (AFRAX) syndrome; autism-fragile X syndrome; backbone; base; dendrite spine; depression; disease/disorder; fra(X) syndrome; fra(X)(28) syndrome; fra(X)(q27) syndrome; fra(X)(q27-28) syndrome; fragile X mental retardation 1; fragile X mental retardation-1 protein; fragile X-mental retardation syndrome; fragile Xq syndrome; fragile site mental retardation 1; fragile x [{C0016667}]; fragile x syndromes; gene product; intervention development; juvenile; juvenile human; long term depression; loss of function mutation; mRNA; macro-orchidism-marker X (MOMX) syndrome; macro-orchidism-marker X syndrome; mar(X) syndrome; marker X syndrome; mature animal; mental retardation-macroorchidism syndrome; metabotropic glutamate receptor type 1; mouse model; mutant; neurobiological; neuronal; new therapeutics; next generation therapeutics; novel; novel therapeutics; postnatal; postsynaptic; protein expression; protein function; protein synthesis; response; social role; synapse formation; synapse function; synaptic depression; synaptic function; synaptogenesis; t-PA; therapy development; treatment development; treatment strategy
Project start date: 2009-09-30
Project end date: 2010-09-29
Budget start date: 30-SEP-2009
Budget end date: 29-SEP-2010
PFA/PA: PA-07-284
3R01HD052731-02S1 (2009): $82270
MECHANISMS OF MGLUR-DEPENDENT SYNAPTIC PLASTICITY
Kimberly M Huber
University Of Texas Sw Med Ctr/dallas, Dallas, Tx 75390-9105
Grant 5R01NS045711-08 from National Institute Of Neurological Disorders And Stroke
Abstract: Activation of the Gq coupled metabotropic glutamate receptors (Group 1 mGluRs) induce long-term plasticity of neuronal and synaptic function which is mediated through direct regulation of new protein synthesis. Consequently, the group 1 mGluRs, mGluR1 and mGluR5 are implicated many long-term behavioral adaptions of brain function including postnatal cortical map formation, learning and memory, chronic pain and drug addiction. Elucidating the basic mechanisms of how mGluRs and other Gq coupled neurotransmitter receptors induce plasticity and how these new proteins alter synapse function is essential to understanding the neurobiological basis of these behaviors. The significance of mGluR- dependent plasticity to human cognitive function is highlighted by the recent findings of enhanced or unregulated mGluR-and protein synthesis dependent plasticity in the mouse model of fragile X syndrome (Fmr1 KO mice), the most common inherited form of mental retardation in humans. We have discovered and characterized a form of long-term synaptic depression in hippocampal area CA1 induced by group 1 mGluRs which relies on rapid (within minutes) protein synthesis in dendrites (mGluR-LTD). Furthermore, we have found that the mechanisms of mGluR-LTD are altered in Fmr1 KO mice. This proposal focuses on determining how mGluRs induce LTD and regulate protein synthesis machinery and how new proteins lead to persistent changes at synapses. Based on our new findings, we hypothesize and propose experiments to test if other Gq coupled neurotransmitter receptors induce LTD through similar mechanisms as group 1 mGluRs. From the knowledge gained from the study of the basic mechanisms of mGluR-LTD in normal rodents, we propose experiments to examine how and why mGluR-dependent plasticity is altered in Fmr1 KO mice. 1 Determine the role of Homer isoforms in mGluR-and protein synthesis dependent LTD mechanisms. 2 Determine mechanism for persistent decreases in AMPAR surface expression induced by mGluRs. 3 Explore the role of other Gq coupled receptors in protein synthesis dependent LTD .4 Role of Homer interactions and other Gq coupled receptors in LTD in Fmr1 KO mice
Keywords: AMPA Receptors; Acute; Addiction, Drug; Agonist; Ammon Horn; Area; Behavior; Behavioral; Brain; C-terminal; CNS plasticity; Cell Communication and Signaling; Cell Signaling; Chemical Dependence; Complex; Cornu Ammonis; Coupled; Data; Dendrites; Dependence, Drug; Drug Addiction; Drug Dependency; Encephalon; Encephalons; Endocytosis; Escalante syndrome; FMR1; Fmr1, ; Fragile X; Fragile X Syndrome; Glutamates; Hereditary; Hippocampus; Hippocampus (Brain); Homer 2; Human; Human, General; Inherited; Intracellular Communication and Signaling; Investigators; Isoforms; Knowledge; L-Glutamate; Lead; Learning; Long-Term Depression (Neurophysiology); Long-Term Depression (Physiology); Long-Term Synaptic Depression; Mammals, Mice; Mammals, Rodents; Man (Taxonomy); Man, Modern; Maps; Martin-Bell Syndrome; Martin-Bell-Renpenning syndrome; Mediating; Memory; Mental Retardation; Metabotropic Glutamate Receptors; Mice; Molecular; Murine; Mus; Nerve Transmitter Substances; Nervous System, Brain; Neurobiology; Neuromediator Receptors; Neuronal Plasticity; Neuroregulator Receptors; Neurotransmitter Receptor; Neurotransmitters; Pb element; Peptide Biosynthesis, Ribosomal; Peptides; Protein Biosynthesis; Protein Biosynthesis, Ribosomal; Protein Family; Protein Isoforms; Protein Synthesis Induction; Protein Synthesis, Ribosomal; Proteins; Receptors, Neurohumor; Regulation; Renpenning syndrome 2; Research Personnel; Researchers; Rodent; Rodentia; Rodentias; Role; Scaffolding Protein; Signal Transduction; Signal Transduction Systems; Signaling; Surface; Synapses; Synaptic; Synaptic plasticity; System; System, LOINC Axis 4; Tail; Testing; Vesl-2; X-linked mental deficiency-megalotestes syndrome; X-linked mental retardation with fragile X syndrome; X-linked mental retardation-fragile site 1 syndrome; autism-fragile X (AFRAX) syndrome; autism-fragile X syndrome; base; biological signal transduction; chronic pain; chronic painful condition; cognitive function; cupidin; density; experiment; experimental research; experimental study; fra(X) syndrome; fra(X)(28) syndrome; fra(X)(q27) syndrome; fra(X)(q27-28) syndrome; fragile X-mental retardation syndrome; fragile Xq syndrome; fragile site mental retardation 1; fragile x [{C0016667}]; fragile x syndromes; gene product; heavy metal Pb; heavy metal lead; hippocampal; long term depression; macro-orchidism-marker X (MOMX) syndrome; macro-orchidism-marker X syndrome; mar(X) syndrome; marker X syndrome; mental retardation-macroorchidism syndrome; mouse model; neural plasticity; neurobiological; neuroplasticity; postnatal; postsynaptic; protein synthesis; receptor coupling; receptor expression; research study; social role; synapse function; synaptic function; trafficking
Project start date: 2003-04-01
Project end date: 2011-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: PA-05-108
5R01NS045711-08 (2010): $310860
5R01NS045711-07 (2009): $314000
3R01NS045711-06S1 (2009): $69662
5R01NS045711-06 (2008): $314000
2R01NS045711-05A1 (2007): $314000
Sponsored Links Excellgen http://Excellgen.com
Kimberly M Huber
University Of Texas Sw Med Ctr/dallas
Project start date: 2008-02-08
Project end date: 2013-01-31
STUDY OF FRAGILE X MENTAL RETARDATION PROTEIN IN SYNAPTIC FUNCTION AND PLASTICITY
Kimberly M Huber
University Of Texas Sw Med Ctr/dallas, Dallas, Tx 75390-9105
Grant 5R01HD052731-03 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Keywords: 21+ years old; Acute; Adolescent; Adolescent Youth; Adult; Animal Welfare; Assay; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Bibliography; Bioassay; Biologic Assays; Biological Assay; Brain; Cells; Cognitive deficits; Country; Dendrites; Dendritic Spines; Development; Disease; Disorder; Dose; Ecological impact; Encephalon; Encephalons; Environment; Environmental Impact; Equipment; Escalante syndrome; Esteroproteases; Ethics Committees, Research; FMR-1 Protein; FMR1; FMR1 Gene; FMR1 Protein; FMR1 protein, fragile X; FMRP protein; Fmr1 gene, ; Fmr1, ; Fragile X; Fragile X Mental Retardation 1 Gene; Fragile X Mental Retardation Protein; Fragile X Syndrome; Grant; Hereditary; Human, Adult; IACUC; IRBs; Impact, Environmental; Inherited; Institutional Animal Care and Use Committee; Institutional Review Boards; International; Kanner`s Syndrome; Knock-out; Knockout; Knockout Mice; Knowledge; Literature; Long-Term Depression (Neurophysiology); Long-Term Depression (Physiology); Long-Term Synaptic Depression; Mammals, Mice; Martin-Bell Syndrome; Martin-Bell-Renpenning syndrome; Measurement; Mediating; Mental Retardation; Metabotropic Glutamate Receptors; Mice; Mice, Knock-out; Mice, Knockout; Mission; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurobiology; Neurocyte; Neurons; Null Mouse; PAI-1; PAI1; PI12 gene product; PLANH1; PLAU; Patients; Peptidases; Peptide Biosynthesis, Ribosomal; Peptide Hydrolases; Phosphorylation; Plasminogen Activator Inhibitor 1; Plasminogen Activator, Urokinase; Principal Investigator; Programs (PT); Programs [Publication Type]; Proteases; Protein Biosynthesis; Protein Biosynthesis, Ribosomal; Protein Phosphorylation; Protein Synthesis, Ribosomal; Proteinases; Proteins; Proteolytic Enzymes; RNA-Binding Proteins; Receptors, Metabotropic Glutamate; Recombinants; Regulation; Renpenning syndrome 2; Research; Research Ethics Committees; Research Resources; Resources; Role; Serine or Cysteine Proteinase Inhibitor Clade E Member 1; Slice; Specificity; Spinal Column; Spine; Synapses; Synaptic; Synaptic plasticity; Testing; Therapeutic; Translational Regulation; Translations; Tripcellim; Trypsin; Type 1 Plasminogen Activator Inhibitor; U-PA; U-Plasminogen Activator; UPA; United States National Institutes of Health; Urinary Plasminogen Activator; Urokinase; Urokinase-Type Plasminogen Activator; Vertebral column; Vertebrate Animals; Vertebrates; X-linked mental deficiency-megalotestes syndrome; X-linked mental retardation with fragile X syndrome; X-linked mental retardation-fragile site 1 syndrome; ing; adult animal; adult human (21+); autism-fragile X (AFRAX) syndrome; autism-fragile X syndrome; backbone; base; dendrite spine; disease/disorder; experiment; experimental research; experimental study; expiration; fra(X) syndrome; fra(X)(28) syndrome; fra(X)(q27) syndrome; fra(X)(q27-28) syndrome; fragile X mental retardation 1; fragile X mental retardation-1 protein; fragile X-mental retardation syndrome; fragile Xq syndrome; fragile site mental retardation 1; fragile x [{C0016667}]; fragile x syndromes; gene product; human subject; inhibitor; inhibitor/antagonist; juvenile; juvenile human; long term depression; loss of function mutation; macro-orchidism-marker X (MOMX) syndrome; macro-orchidism-marker X syndrome; mar(X) syndrome; marker X syndrome; mature animal; mental retardation-macroorchidism syndrome; neurobiological; neuronal; neuroserpin; new therapeutics; next generation therapeutics; novel therapeutics; postsynaptic; programs; protein synthesis; research study; response; social role; synapse function; synaptic depression; synaptic function; treatment strategy; vertebrata
Project start date: 2008-02-08
Project end date: 2013-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-284
5R01HD052731-03 (2010): $392087