RT Journal Article
SR Electronic
T1 Transient and Progressive Electrophysiological Alterations in the Corticostriatal Pathway in a Mouse Model of Huntington's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 961
OP 969
DO 10.1523/JNEUROSCI.23-03-00961.2003
VO 23
IS 3
A1 Cepeda, Carlos
A1 Hurst, Raymond S.
A1 Calvert, Christopher R.
A1 Hernández-Echeagaray, Elizabeth
A1 Nguyen, Oanh K.
A1 Jocoy, Emily
A1 Christian, Lindsey J.
A1 Ariano, Marjorie A.
A1 Levine, Michael S.
YR 2003
UL http://www.jneurosci.org/content/23/3/961.abstract
AB 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.