Subthalamic GAD Gene Therapy in a Parkinson's Disease Rat Model
The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal ganglia network activity, including disinhibition of the subthalamic nucleus (STN), and excessive activity of the major output nuclei. Using adeno-associated viral vector-mediated somatic cell gene transfer,...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2002-10, Vol.298 (5592), p.425-429 |
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| creator | Luo, Jia Kaplitt, Michael G. Fitzsimons, Helen L. Zuzga, David S. Liu, Yuhong Oshinsky, Michael L. During, Matthew J. |
| description | The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal ganglia network activity, including disinhibition of the subthalamic nucleus (STN), and excessive activity of the major output nuclei. Using adeno-associated viral vector-mediated somatic cell gene transfer, we expressed glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the neurotransmitter GABA, in excitatory glutamatergic neurons of the STN in rats. The transduced neurons, when driven by electrical stimulation, produced mixed inhibitory responses associated with GABA release. This phenotypic shift resulted in strong neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype. This strategy suggests that there is plasticity between excitatory and inhibitory neurotransmission in the mammalian brain that could be exploited for therapeutic benefit. |
| doi_str_mv | 10.1126/science.1074549 |
| format | Article |
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Using adeno-associated viral vector-mediated somatic cell gene transfer, we expressed glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the neurotransmitter GABA, in excitatory glutamatergic neurons of the STN in rats. The transduced neurons, when driven by electrical stimulation, produced mixed inhibitory responses associated with GABA release. This phenotypic shift resulted in strong neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype. This strategy suggests that there is plasticity between excitatory and inhibitory neurotransmission in the mammalian brain that could be exploited for therapeutic benefit.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1074549</identifier><identifier>PMID: 12376704</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Association for the Advancement of Science</publisher><subject>Animals ; Behavioral neuroscience ; Biological and medical sciences ; Brain ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Dependovirus - genetics ; Disease Models, Animal ; Dopamine - metabolism ; Electric Stimulation ; Electrodes ; Electrophysiology ; Enzymes ; Feedback (Response) ; gamma-Aminobutyric Acid - metabolism ; Gene therapy ; Genetic aspects ; Genetic Therapy ; Genetic Vectors ; Glutamate Decarboxylase - genetics ; Glutamate Decarboxylase - metabolism ; Glutamic Acid - metabolism ; Humans ; Ibotenic Acid - pharmacology ; Inhibition ; Isoenzymes - genetics ; Isoenzymes - metabolism ; Lesions ; Male ; Medical sciences ; Mesencephalon - metabolism ; Mesencephalon - pathology ; Mice ; Motor Activity - drug effects ; Nerve Degeneration ; Neurology ; Neurons ; Neurons - metabolism ; Oxidopamine - pharmacology ; Parkinson disease ; Parkinson's disease ; Parkinsonian Disorders - metabolism ; Parkinsonian Disorders - pathology ; Parkinsonian Disorders - therapy ; Phenotype ; Phenotypes ; Rats ; Rodents ; Stem Cells - virology ; Substantia Nigra - metabolism ; Substantia Nigra - pathology ; Substantia Nigra - physiopathology ; Subthalamic Nucleus - metabolism ; Subthalamic Nucleus - pathology ; Supernova remnants ; Synaptic Transmission ; Transgenes ; Ventral tegmental area</subject><ispartof>Science (American Association for the Advancement of Science), 2002-10, Vol.298 (5592), p.425-429</ispartof><rights>Copyright 2002 American Association for the Advancement of Science</rights><rights>2002 INIST-CNRS</rights><rights>COPYRIGHT 2002 American Association for the Advancement of Science</rights><rights>COPYRIGHT 2002 American Association for the Advancement of Science</rights><rights>Copyright American Association for the Advancement of Science Oct 11, 2002</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c774t-ac75f9e4f9787cea1f367a92b6e03fbc93dbc7205218b5f88904365f77d2f6ae3</citedby><cites>FETCH-LOGICAL-c774t-ac75f9e4f9787cea1f367a92b6e03fbc93dbc7205218b5f88904365f77d2f6ae3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3832554$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3832554$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,780,784,803,2884,2885,27924,27925,58017,58250</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13983946$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12376704$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Luo, Jia</creatorcontrib><creatorcontrib>Kaplitt, Michael G.</creatorcontrib><creatorcontrib>Fitzsimons, Helen L.</creatorcontrib><creatorcontrib>Zuzga, David S.</creatorcontrib><creatorcontrib>Liu, Yuhong</creatorcontrib><creatorcontrib>Oshinsky, Michael L.</creatorcontrib><creatorcontrib>During, Matthew J.</creatorcontrib><title>Subthalamic GAD Gene Therapy in a Parkinson's Disease Rat Model</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal ganglia network activity, including disinhibition of the subthalamic nucleus (STN), and excessive activity of the major output nuclei. Using adeno-associated viral vector-mediated somatic cell gene transfer, we expressed glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the neurotransmitter GABA, in excitatory glutamatergic neurons of the STN in rats. The transduced neurons, when driven by electrical stimulation, produced mixed inhibitory responses associated with GABA release. This phenotypic shift resulted in strong neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype. This strategy suggests that there is plasticity between excitatory and inhibitory neurotransmission in the mammalian brain that could be exploited for therapeutic benefit.</description><subject>Animals</subject><subject>Behavioral neuroscience</subject><subject>Biological and medical sciences</subject><subject>Brain</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Dependovirus - genetics</subject><subject>Disease Models, Animal</subject><subject>Dopamine - metabolism</subject><subject>Electric Stimulation</subject><subject>Electrodes</subject><subject>Electrophysiology</subject><subject>Enzymes</subject><subject>Feedback (Response)</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Gene therapy</subject><subject>Genetic aspects</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors</subject><subject>Glutamate Decarboxylase - genetics</subject><subject>Glutamate Decarboxylase - metabolism</subject><subject>Glutamic Acid - metabolism</subject><subject>Humans</subject><subject>Ibotenic Acid - pharmacology</subject><subject>Inhibition</subject><subject>Isoenzymes - genetics</subject><subject>Isoenzymes - metabolism</subject><subject>Lesions</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mesencephalon - metabolism</subject><subject>Mesencephalon - 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Luo, Jia</au><au>Kaplitt, Michael G.</au><au>Fitzsimons, Helen L.</au><au>Zuzga, David S.</au><au>Liu, Yuhong</au><au>Oshinsky, Michael L.</au><au>During, Matthew J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Subthalamic GAD Gene Therapy in a Parkinson's Disease Rat Model</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2002-10-11</date><risdate>2002</risdate><volume>298</volume><issue>5592</issue><spage>425</spage><epage>429</epage><pages>425-429</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><abstract>The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal ganglia network activity, including disinhibition of the subthalamic nucleus (STN), and excessive activity of the major output nuclei. Using adeno-associated viral vector-mediated somatic cell gene transfer, we expressed glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the neurotransmitter GABA, in excitatory glutamatergic neurons of the STN in rats. The transduced neurons, when driven by electrical stimulation, produced mixed inhibitory responses associated with GABA release. This phenotypic shift resulted in strong neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype. This strategy suggests that there is plasticity between excitatory and inhibitory neurotransmission in the mammalian brain that could be exploited for therapeutic benefit.</abstract><cop>Washington, DC</cop><pub>American Association for the Advancement of Science</pub><pmid>12376704</pmid><doi>10.1126/science.1074549</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2002-10, Vol.298 (5592), p.425-429 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_743435397 |
| source | MEDLINE; JSTOR Archive Collection A-Z Listing; American Association for the Advancement of Science |
| subjects | Animals Behavioral neuroscience Biological and medical sciences Brain Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Dependovirus - genetics Disease Models, Animal Dopamine - metabolism Electric Stimulation Electrodes Electrophysiology Enzymes Feedback (Response) gamma-Aminobutyric Acid - metabolism Gene therapy Genetic aspects Genetic Therapy Genetic Vectors Glutamate Decarboxylase - genetics Glutamate Decarboxylase - metabolism Glutamic Acid - metabolism Humans Ibotenic Acid - pharmacology Inhibition Isoenzymes - genetics Isoenzymes - metabolism Lesions Male Medical sciences Mesencephalon - metabolism Mesencephalon - pathology Mice Motor Activity - drug effects Nerve Degeneration Neurology Neurons Neurons - metabolism Oxidopamine - pharmacology Parkinson disease Parkinson's disease Parkinsonian Disorders - metabolism Parkinsonian Disorders - pathology Parkinsonian Disorders - therapy Phenotype Phenotypes Rats Rodents Stem Cells - virology Substantia Nigra - metabolism Substantia Nigra - pathology Substantia Nigra - physiopathology Subthalamic Nucleus - metabolism Subthalamic Nucleus - pathology Supernova remnants Synaptic Transmission Transgenes Ventral tegmental area |
| title | Subthalamic GAD Gene Therapy in a Parkinson's Disease Rat Model |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T19%3A02%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Subthalamic%20GAD%20Gene%20Therapy%20in%20a%20Parkinson's%20Disease%20Rat%20Model&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Luo,%20Jia&rft.date=2002-10-11&rft.volume=298&rft.issue=5592&rft.spage=425&rft.epage=429&rft.pages=425-429&rft.issn=0036-8075&rft.eissn=1095-9203&rft.coden=SCIEAS&rft_id=info:doi/10.1126/science.1074549&rft_dat=%3Cgale_proqu%3EA93349521%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=213594455&rft_id=info:pmid/12376704&rft_galeid=A93349521&rft_jstor_id=3832554&rfr_iscdi=true |