LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory.
Identifieur interne : 000665 ( Main/Exploration ); précédent : 000664; suivant : 000666LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory.
Auteurs : Dayne A. Beccano-Kelly ; Mattia Volta ; Lise N. Munsie ; Sarah A. Paschall ; Igor Tatarnikov ; Kimberley Co ; Patrick Chou ; Li-Ping Cao ; Sabrina Bergeron ; Emma Mitchell ; Heather Han ; Heather L. Melrose [États-Unis] ; Lucia Tapia ; Lynn A. Raymond [Canada] ; Matthew J. Farrer ; Austen J. Milnerwood [Canada]Source :
- Human molecular genetics [ 1460-2083 ] ; 2015.
English descriptors
- KwdEn :
- Animals, Dopamine (metabolism), Glutamates, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Memory, Mice, Mice, Transgenic, Motor Activity, Neostriatum (metabolism), Neuronal Plasticity, Neurons (metabolism), Parkinson Disease (genetics), Phosphoproteins (genetics), Phosphoproteins (metabolism), Protein-Serine-Threonine Kinases (genetics), Protein-Serine-Threonine Kinases (metabolism), Receptors, Dopamine D2 (genetics), Receptors, Dopamine D2 (metabolism), Signal Transduction, Synaptic Transmission.
- MESH :
- chemical , genetics : Phosphoproteins, Protein-Serine-Threonine Kinases, Receptors, Dopamine D2.
- chemical , metabolism : Dopamine, Phosphoproteins, Protein-Serine-Threonine Kinases, Receptors, Dopamine D2.
- genetics : Parkinson Disease.
- metabolism : Neostriatum, Neurons.
- Animals, Glutamates, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Memory, Mice, Mice, Transgenic, Motor Activity, Neuronal Plasticity, Signal Transduction, Synaptic Transmission.
Abstract
Mutations in leucine-rich repeat kinase 2 (Lrrk2) are the most common genetic cause of Parkinson's disease (PD), a neurodegenerative disorder affecting 1-2% of those >65 years old. The neurophysiology of LRRK2 remains largely elusive, although protein loss suggests a role in glutamatergic synapse transmission and overexpression studies show altered dopamine release in aged mice. We show that glutamate transmission is unaltered onto striatal projection neurons (SPNs) of adult LRRK2 knockout mice and that adult animals exhibit no detectable cognitive or motor deficits. Basal synaptic transmission is also unaltered in SPNs of LRRK2 overexpressing mice, but they do exhibit clear alterations to D2-receptor-mediated short-term synaptic plasticity, behavioral hypoactivity and impaired recognition memory. These phenomena are associated with decreased striatal dopamine tone and abnormal dopamine- and cAMP-regulated phosphoprotein 32 kDa signal integration. The data suggest that LRRK2 acts at the nexus of dopamine and glutamate signaling in the adult striatum, where it regulates dopamine levels, presynaptic glutamate release via D2-dependent synaptic plasticity and dopamine-receptor signal transduction.
DOI: 10.1093/hmg/ddu543
PubMed: 25343991
Affiliations:
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Beccano-Kelly</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Volta, Mattia" sort="Volta, Mattia" uniqKey="Volta M" first="Mattia" last="Volta">Mattia Volta</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Munsie, Lise N" sort="Munsie, Lise N" uniqKey="Munsie L" first="Lise N" last="Munsie">Lise N. Munsie</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Paschall, Sarah A" sort="Paschall, Sarah A" uniqKey="Paschall S" first="Sarah A" last="Paschall">Sarah A. Paschall</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Tatarnikov, Igor" sort="Tatarnikov, Igor" uniqKey="Tatarnikov I" first="Igor" last="Tatarnikov">Igor Tatarnikov</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Co, Kimberley" sort="Co, Kimberley" uniqKey="Co K" first="Kimberley" last="Co">Kimberley Co</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Chou, Patrick" sort="Chou, Patrick" uniqKey="Chou P" first="Patrick" last="Chou">Patrick Chou</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Cao, Li Ping" sort="Cao, Li Ping" uniqKey="Cao L" first="Li-Ping" last="Cao">Li-Ping Cao</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Bergeron, Sabrina" sort="Bergeron, Sabrina" uniqKey="Bergeron S" first="Sabrina" last="Bergeron">Sabrina Bergeron</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Mitchell, Emma" sort="Mitchell, Emma" uniqKey="Mitchell E" first="Emma" last="Mitchell">Emma Mitchell</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Han, Heather" sort="Han, Heather" uniqKey="Han H" first="Heather" last="Han">Heather Han</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Melrose, Heather L" sort="Melrose, Heather L" uniqKey="Melrose H" first="Heather L" last="Melrose">Heather L. Melrose</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224</wicri:regionArea><placeName><region type="state">Floride</region></placeName></affiliation></author><author><name sortKey="Tapia, Lucia" sort="Tapia, Lucia" uniqKey="Tapia L" first="Lucia" last="Tapia">Lucia Tapia</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre.</nlm:affiliation><wicri:noCountry code="subField">Brain Research Centre</wicri:noCountry></affiliation></author><author><name sortKey="Raymond, Lynn A" sort="Raymond, Lynn A" uniqKey="Raymond L" first="Lynn A" last="Raymond">Lynn A. Raymond</name><affiliation wicri:level="1"><nlm:affiliation>Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, Canada V6T 2B5.</nlm:affiliation><country>Canada</country><wicri:regionArea>Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver</wicri:regionArea><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author><author><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J" last="Farrer">Matthew J. Farrer</name><affiliation><nlm:affiliation>Centre for Applied Neurogenetics, Brain Research Centre, Department of Medical Genetics.</nlm:affiliation><wicri:noCountry code="subField">Department of Medical Genetics</wicri:noCountry></affiliation></author><author><name sortKey="Milnerwood, Austen J" sort="Milnerwood, Austen J" uniqKey="Milnerwood A" first="Austen J" last="Milnerwood">Austen J. Milnerwood</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Applied Neurogenetics, Division of Neurology, Brain Research Centre, amilnerwood@can.ubc.ca.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>Centre for Applied Neurogenetics, Division of Neurology, Brain Research Centre</wicri:regionArea><wicri:noRegion>Brain Research Centre</wicri:noRegion></affiliation></author></analytic><series><title level="j">Human molecular genetics</title><idno type="eISSN">1460-2083</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Dopamine (metabolism)</term><term>Glutamates</term><term>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</term><term>Male</term><term>Memory</term><term>Mice</term><term>Mice, Transgenic</term><term>Motor Activity</term><term>Neostriatum (metabolism)</term><term>Neuronal Plasticity</term><term>Neurons (metabolism)</term><term>Parkinson Disease (genetics)</term><term>Phosphoproteins (genetics)</term><term>Phosphoproteins (metabolism)</term><term>Protein-Serine-Threonine Kinases (genetics)</term><term>Protein-Serine-Threonine Kinases (metabolism)</term><term>Receptors, Dopamine D2 (genetics)</term><term>Receptors, Dopamine D2 (metabolism)</term><term>Signal Transduction</term><term>Synaptic Transmission</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Phosphoproteins</term><term>Protein-Serine-Threonine Kinases</term><term>Receptors, Dopamine D2</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dopamine</term><term>Phosphoproteins</term><term>Protein-Serine-Threonine Kinases</term><term>Receptors, Dopamine D2</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neostriatum</term><term>Neurons</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Glutamates</term><term>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</term><term>Male</term><term>Memory</term><term>Mice</term><term>Mice, Transgenic</term><term>Motor Activity</term><term>Neuronal Plasticity</term><term>Signal Transduction</term><term>Synaptic Transmission</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in leucine-rich repeat kinase 2 (Lrrk2) are the most common genetic cause of Parkinson's disease (PD), a neurodegenerative disorder affecting 1-2% of those >65 years old. The neurophysiology of LRRK2 remains largely elusive, although protein loss suggests a role in glutamatergic synapse transmission and overexpression studies show altered dopamine release in aged mice. We show that glutamate transmission is unaltered onto striatal projection neurons (SPNs) of adult LRRK2 knockout mice and that adult animals exhibit no detectable cognitive or motor deficits. Basal synaptic transmission is also unaltered in SPNs of LRRK2 overexpressing mice, but they do exhibit clear alterations to D2-receptor-mediated short-term synaptic plasticity, behavioral hypoactivity and impaired recognition memory. These phenomena are associated with decreased striatal dopamine tone and abnormal dopamine- and cAMP-regulated phosphoprotein 32 kDa signal integration. The data suggest that LRRK2 acts at the nexus of dopamine and glutamate signaling in the adult striatum, where it regulates dopamine levels, presynaptic glutamate release via D2-dependent synaptic plasticity and dopamine-receptor signal transduction.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Floride</li></region></list><tree><noCountry><name sortKey="Beccano Kelly, Dayne A" sort="Beccano Kelly, Dayne A" uniqKey="Beccano Kelly D" first="Dayne A" last="Beccano-Kelly">Dayne A. Beccano-Kelly</name><name sortKey="Bergeron, Sabrina" sort="Bergeron, Sabrina" uniqKey="Bergeron S" first="Sabrina" last="Bergeron">Sabrina Bergeron</name><name sortKey="Cao, Li Ping" sort="Cao, Li Ping" uniqKey="Cao L" first="Li-Ping" last="Cao">Li-Ping Cao</name><name sortKey="Chou, Patrick" sort="Chou, Patrick" uniqKey="Chou P" first="Patrick" last="Chou">Patrick Chou</name><name sortKey="Co, Kimberley" sort="Co, Kimberley" uniqKey="Co K" first="Kimberley" last="Co">Kimberley Co</name><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J" last="Farrer">Matthew J. Farrer</name><name sortKey="Han, Heather" sort="Han, Heather" uniqKey="Han H" first="Heather" last="Han">Heather Han</name><name sortKey="Mitchell, Emma" sort="Mitchell, Emma" uniqKey="Mitchell E" first="Emma" last="Mitchell">Emma Mitchell</name><name sortKey="Munsie, Lise N" sort="Munsie, Lise N" uniqKey="Munsie L" first="Lise N" last="Munsie">Lise N. Munsie</name><name sortKey="Paschall, Sarah A" sort="Paschall, Sarah A" uniqKey="Paschall S" first="Sarah A" last="Paschall">Sarah A. Paschall</name><name sortKey="Tapia, Lucia" sort="Tapia, Lucia" uniqKey="Tapia L" first="Lucia" last="Tapia">Lucia Tapia</name><name sortKey="Tatarnikov, Igor" sort="Tatarnikov, Igor" uniqKey="Tatarnikov I" first="Igor" last="Tatarnikov">Igor Tatarnikov</name><name sortKey="Volta, Mattia" sort="Volta, Mattia" uniqKey="Volta M" first="Mattia" last="Volta">Mattia Volta</name></noCountry><country name="États-Unis"><region name="Floride"><name sortKey="Melrose, Heather L" sort="Melrose, Heather L" uniqKey="Melrose H" first="Heather L" last="Melrose">Heather L. Melrose</name></region></country><country name="Canada"><noRegion><name sortKey="Raymond, Lynn A" sort="Raymond, Lynn A" uniqKey="Raymond L" first="Lynn A" last="Raymond">Lynn A. Raymond</name></noRegion><name sortKey="Milnerwood, Austen J" sort="Milnerwood, Austen J" uniqKey="Milnerwood A" first="Austen J" last="Milnerwood">Austen J. Milnerwood</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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