Search

Altered neuronal activity in the striatum appears to be a key component of Huntington's disease (HD), a fatal, neurodegenerative condition. To assess this hypothesis in freely behaving transgenic rats that model HD (tgHDs), we used chronically implanted micro-wires to record the spontaneous activity of striatal neurons. We found that relative to wild-type controls, HD rats suffer from population-level deficits in striatal activity characterized by a loss of correlated firing and fewer episodes of coincident spike bursting between simultaneously recorded neuronal pairs. These results are in line with our previous report of marked alterations in the pattern of striatal firing in mouse models of HD that vary in background strain, genetic construct, and symptom severity. Thus, loss of coordinated spike activity in striatum appears to be a common feature of HD pathophysiology, regardless of HD model variability.

Huntington's disease (HD) is an autosomal dominant condition that compromises behavioral output. Dysfunction of medium spiny neurons (MSNs), which are the sole output system of the striatum, is thought to underlie HD pathophysiology. What is not known is how HD alters MSN information processing during behavior, which likely drives the HD behavioral phenotype. We recorded from populations of MSNs in two freely behaving and symptomatic HD mouse models: R6/2 transgenics are based on a C57BL/6J*CBA/J background and show robust behavioral symptoms, whereas knock-in (KI) mice have a 129sv background and express relatively mild behavioral signs. At the single-unit level, we found that the MSN firing rate was elevated in R6/2 but not in KI mice compared with their respective wild-type (WT) controls. In contrast, burst activity, which corresponds to periods of high-frequency firing, was altered in both HD models compared with WT. At the population level, we found that correlated firing between pairs of MSNs was a prominent feature in WT that was reduced in both HD models. Similarly, coincident bursts, which are bursts between pairs of neurons that overlap in time and occur more often in pairs of MSNs that exhibit correlated firing, were decreased in HD mice. Our results indicate an important role in both bursting and correlated burst firing for information processing in MSNs. Dysregulation of this processing scheme, moreover, is a key component of HD pathophysiology regardless of the severity of HD symptoms, genetic construct, and background strain of the mouse models.

Understanding cortical information processing in Huntington's disease (HD), a genetic neurological disorder characterized by prominent motor and cognitive abnormalities, is key to understanding the mechanisms underlying the HD behavioral phenotype. We recorded extracellular spike activity in two symptomatic, freely behaving mouse models: R6/2 transgenics, which are based on a CBA x C57BL/6 background and show robust behavioral symptoms, and HD knock-in (KI) mice, which have a 129sv background and express relatively mild behavioral signs. We focused on prefrontal cortex and assessed firing patterns of individually recorded neurons as well as the amount of synchrony between simultaneously recorded neuronal pairs. At the single-unit level, spike trains in R6/2 transgenics were less variable and had a faster rate than their corresponding wild-type (WT) littermates but showed significantly less bursting. In contrast, KI and WT firing patterns were closely matched. An assessment of both WTs revealed that the R6/2 and KI difference could not be explained by a difference in WT electrophysiology. Thus, the altered pattern of individual spike trains in R6/2 mice appears to parallel their aggressive form of symptom expression. Both WT lines, however, showed a high proportion of synchrony between neuronal pairs (>85%) that was significantly attenuated in both corresponding HD models (decreases of approximately 20% and approximately 30% in R6/2s and knock-ins, respectively). The loss of spike synchrony, regardless of symptom severity, suggests a population-level deficit in cortical information processing that underlies HD progression.