Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's disease

Carlos Cepeda, Raymond S. Hurst, Christopher R. Calvert, Elizabeth Hernández-Echeagaray, Oanh K. Nguyen, Emily Jocoy, Lindsey J. Christian, Marjorie A. Ariano, Michael S. Levine

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Abstract

Alterations in the corticostriatal pathway may precede symptomatology and striatal cell death in Huntington's disease (HD) patients. Here we examined spontaneous EPSCs in striatal medium-sized spiny neurons in slices from a mouse model of HD (R6/2). Spontaneous EPSC frequency was similar in young (3-4 weeks) transgenics and controls but decreased significantly in transgenics when overt behavioral symptoms began (5-7 weeks) and was most pronounced in severely impaired transgenics (11-15 weeks). These differences were maintained after bicuculline or tetrodotoxin, indicating they were specific to glutamatergic input and likely presynaptic in origin. Decreases in presynaptic and postsynaptic protein markers, synaptophysin and postsynaptic density-95, occurred in 11-15 week R6/2 mice, supporting the electrophysiological results. Furthermore, isolated, large-amplitude synaptic events (>100 pA) occurred more frequently in transgenic animals, particularly at 5-7 weeks, suggesting additional dysregulation of cortical inputs. Large events were blocked by tetrodotoxin, indicating a possible cortical origin. Addition of bicuculline and 4-aminopyridine facilitated the occurrence of large events. Riluzole, a compound that decreases glutamate release, reduced these events. Together, these observations indicate that both progressive and transient alterations occur along the corticostriatal pathway in experimental HD. These alterations are likely to contribute to the selective vulnerability of striatal medium-sized spiny neurons.

Original languageEnglish (US)
Pages (from-to)961-969
Number of pages9
JournalJournal of Neuroscience
Volume23
Issue number3
StatePublished - Feb 1 2003

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Keywords

  • Corticostriatal pathway
  • EPSCSs
  • Glutamatergic activity
  • Huntington's disease
  • Mouse models
  • R6/2

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Cepeda, C., Hurst, R. S., Calvert, C. R., Hernández-Echeagaray, E., Nguyen, O. K., Jocoy, E., Christian, L. J., Ariano, M. A., & Levine, M. S. (2003). Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's disease. Journal of Neuroscience, 23(3), 961-969.