Corticostriatal synaptic plasticity alterations in the R6/1 transgenic mouse model of Huntington's disease

Research output: Contribution to journalArticle

Abstract

Huntington's disease (HD) is a genetic neurodegenerative condition characterized by abnormal dopamine (DA)–glutamate interactions, severe alterations in motor control, and reduced behavioral flexibility. Experimental models of disease show that during symptomatic phases, HD shares with other hyperkinetic disorders the loss of synaptic depotentiation in the striatal spiny projection neurons (SPNs). Here we test the hypothesis that corticostriatal long-term depression (LTD), a well-conserved synaptic scaling down response to environmental stimuli, is also altered in symptomatic male R6/1 mice, a HD model with gradual development of symptoms. In vitro patch-clamp and intracellular recordings of corticostriatal slices from R6/1 mice confirm that, similar to other models characterized by hyperkinesia and striatal DA D1 receptor pathway dysregulation, once long-term potentiation (LTP) is induced, synaptic depotentiation is lost. Our new observations show that activity-dependent LTD was abolished in SPNs of mutant mice. In an experimental condition in which N-methyl-d-aspartate (NMDA) receptors are normally not recruited, in vitro bath application of DA revealed an abnormal response of D1 receptors that caused a shift in synaptic plasticity direction resulting in an NMDA-dependent LTP. Our results demonstrate that corticostriatal LTD is lost in R6/1 mouse model and confirm the role of aberrant DA–glutamate interactions in the alterations of synaptic scaling down associated with HD symptoms.

Original languageEnglish
JournalJournal of Neuroscience Research
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Neuronal Plasticity
Huntington Disease
Transgenic Mice
Long-Term Synaptic Depression
Corpus Striatum
Long-Term Potentiation
Depression
Dopamine
Hyperkinesis
Neurons
Dopamine D1 Receptors
Baths
Aspartic Acid
Glutamic Acid
Theoretical Models
In Vitro Techniques

Keywords

  • dopamine-dependent plasticity
  • dorsolateral striatum
  • polyglutamine (polyQ) diseases
  • spiny projection neurons

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

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title = "Corticostriatal synaptic plasticity alterations in the R6/1 transgenic mouse model of Huntington's disease",
abstract = "Huntington's disease (HD) is a genetic neurodegenerative condition characterized by abnormal dopamine (DA)–glutamate interactions, severe alterations in motor control, and reduced behavioral flexibility. Experimental models of disease show that during symptomatic phases, HD shares with other hyperkinetic disorders the loss of synaptic depotentiation in the striatal spiny projection neurons (SPNs). Here we test the hypothesis that corticostriatal long-term depression (LTD), a well-conserved synaptic scaling down response to environmental stimuli, is also altered in symptomatic male R6/1 mice, a HD model with gradual development of symptoms. In vitro patch-clamp and intracellular recordings of corticostriatal slices from R6/1 mice confirm that, similar to other models characterized by hyperkinesia and striatal DA D1 receptor pathway dysregulation, once long-term potentiation (LTP) is induced, synaptic depotentiation is lost. Our new observations show that activity-dependent LTD was abolished in SPNs of mutant mice. In an experimental condition in which N-methyl-d-aspartate (NMDA) receptors are normally not recruited, in vitro bath application of DA revealed an abnormal response of D1 receptors that caused a shift in synaptic plasticity direction resulting in an NMDA-dependent LTP. Our results demonstrate that corticostriatal LTD is lost in R6/1 mouse model and confirm the role of aberrant DA–glutamate interactions in the alterations of synaptic scaling down associated with HD symptoms.",
keywords = "dopamine-dependent plasticity, dorsolateral striatum, polyglutamine (polyQ) diseases, spiny projection neurons",
author = "Veronica Ghiglieri and Federica Campanelli and Gioia Marino and Giuseppina Natale and Barbara Picconi and Paolo Calabresi",
year = "2019",
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doi = "10.1002/jnr.24521",
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T1 - Corticostriatal synaptic plasticity alterations in the R6/1 transgenic mouse model of Huntington's disease

AU - Ghiglieri, Veronica

AU - Campanelli, Federica

AU - Marino, Gioia

AU - Natale, Giuseppina

AU - Picconi, Barbara

AU - Calabresi, Paolo

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Huntington's disease (HD) is a genetic neurodegenerative condition characterized by abnormal dopamine (DA)–glutamate interactions, severe alterations in motor control, and reduced behavioral flexibility. Experimental models of disease show that during symptomatic phases, HD shares with other hyperkinetic disorders the loss of synaptic depotentiation in the striatal spiny projection neurons (SPNs). Here we test the hypothesis that corticostriatal long-term depression (LTD), a well-conserved synaptic scaling down response to environmental stimuli, is also altered in symptomatic male R6/1 mice, a HD model with gradual development of symptoms. In vitro patch-clamp and intracellular recordings of corticostriatal slices from R6/1 mice confirm that, similar to other models characterized by hyperkinesia and striatal DA D1 receptor pathway dysregulation, once long-term potentiation (LTP) is induced, synaptic depotentiation is lost. Our new observations show that activity-dependent LTD was abolished in SPNs of mutant mice. In an experimental condition in which N-methyl-d-aspartate (NMDA) receptors are normally not recruited, in vitro bath application of DA revealed an abnormal response of D1 receptors that caused a shift in synaptic plasticity direction resulting in an NMDA-dependent LTP. Our results demonstrate that corticostriatal LTD is lost in R6/1 mouse model and confirm the role of aberrant DA–glutamate interactions in the alterations of synaptic scaling down associated with HD symptoms.

AB - Huntington's disease (HD) is a genetic neurodegenerative condition characterized by abnormal dopamine (DA)–glutamate interactions, severe alterations in motor control, and reduced behavioral flexibility. Experimental models of disease show that during symptomatic phases, HD shares with other hyperkinetic disorders the loss of synaptic depotentiation in the striatal spiny projection neurons (SPNs). Here we test the hypothesis that corticostriatal long-term depression (LTD), a well-conserved synaptic scaling down response to environmental stimuli, is also altered in symptomatic male R6/1 mice, a HD model with gradual development of symptoms. In vitro patch-clamp and intracellular recordings of corticostriatal slices from R6/1 mice confirm that, similar to other models characterized by hyperkinesia and striatal DA D1 receptor pathway dysregulation, once long-term potentiation (LTP) is induced, synaptic depotentiation is lost. Our new observations show that activity-dependent LTD was abolished in SPNs of mutant mice. In an experimental condition in which N-methyl-d-aspartate (NMDA) receptors are normally not recruited, in vitro bath application of DA revealed an abnormal response of D1 receptors that caused a shift in synaptic plasticity direction resulting in an NMDA-dependent LTP. Our results demonstrate that corticostriatal LTD is lost in R6/1 mouse model and confirm the role of aberrant DA–glutamate interactions in the alterations of synaptic scaling down associated with HD symptoms.

KW - dopamine-dependent plasticity

KW - dorsolateral striatum

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