Transient and Progressive Electrophysiological Alterations in the Corticostriatal Pathway in a Mouse Model of Huntington's Disease

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.

Allosteric activation of M 4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

“…S3A; WT, n = 7; YAC128, n = 9; t test, P < 0.05), an effect that could also increase excitability of YAC128 SPNs at this age. Consistent with previous reports in other HD models (8,12,14), this early alteration of EPSCs was reversed in older animals. Thus, in SPNs recorded in slices from 5-to 6-mo-old YAC128 mice, there was a significant decrease in peak amplitudes of eEPSCs compared with SPNs from WT mice [ Fig.…”

“…At later stages of disease progression, patients experience dystonia, rigidity, and bradykinesia, and ultimately death (3)(4)(5)(6)(7). The cortex and striatum are the most severely affected brain regions in HD and, interestingly, an increasing number of reports suggest that alterations in cortical and striatal physiology are present in prediagnostic individuals and in young HD mice (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

“…This may indicate that the loss of receptors in basal ganglia and cortical regions is partly a consequence of deafferentation from midbrain nuclei. Since there is evidence for a neuroprotective role of both the noradrenergic (Martel et al 1998) and the cholinergic (O'Neill et al 2002) system, the loss of receptors might aggravate the damage caused by excitotoxic glutamatergic flow of cortical projection neurones, which in turn is triggered by the high neocortical load of mutant huntingtin (Cepeda et al 2003).…”

Treatment of Huntington's Disease

“…It is likely that more than one process may be occurring at once, but there is evidence to support multiple individual mechanisms, including toxic neuronal aggregates, transcriptional dysregulation, excitotoxicity, mitochondrial dysfunction with altered energy metabolism, and changes in axonal transport and synaptic dysfunction (Table 2) [24][25][26][27][28][29][30].…”