Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that targets the corticostriatal system and results in progressive deterioration of cognitive, emotional, and motor skills. Although cortical and striatal neurons are widely studied in animal models of HD, there is little information on neuronal function during expression of the HD behavioral phenotype. To address this knowledge gap, we used chronically implanted micro-wire bundles to record extracellular spikes and local field potentials (LFPs) in truncated (R6/1 and R6/2) and full-length (knock-in, KI) mouse models as well as in transgenic HD rats (tgHD rats) behaving in an open-field arena. Spike activity was recorded in the striatum of all models and in prefrontal cortex (PFC) of R6/2 and KI mice, and in primary motor cortex (M1) of R6/2 mice. We also recorded LFP activity in R6/2 striatum. All HD models exhibited altered neuronal activity relative to wild-type (WT) controls. Although there was no consistent effect on firing rate across models and brain areas, burst firing was reduced in striatum, PFC, and M1 of R6/2 mice, and in striatum of KI mice. Consistent with a decline in bursting, the inter-spike-interval coefficient of variation was reduced in all regions of all models, except PFC of KI mice and striatum of tgHD rats. Among simultaneously recorded neuron pairs, correlated firing was reduced in all brain regions of all models, while coincident bursting, which measures the temporal overlap between bursting pairs, was reduced in striatum of all models as well as in M1 of R6/2s. Preliminary analysis of striatal LFPs revealed aberrant behavior-related oscillations in the delta to theta range and in gamma activity. Collectively, our results indicate that disrupted corticostriatal processing occurs across multiple HD models despite differences in the severity of the behavioral phenotype. Efforts aimed at normalizing corticostriatal activity may hold the key to developing new HD therapeutics.
Highlights
The striatum receives input from all areas of cerebral cortex and uses that information to guide behavior
We present early evidence from R6/2 striatum that local field potentials (LFPs), which represent the peri-synaptic activity of a large number of neurons, are altered in Huntington’s disease (HD)
Altered firing properties are apparent at the single-neuron level and at the pair-wise level. These activity patterns are comparable to what we have reported for striatum and prefrontal cortex (PFC) of other HD models (Miller et al, 2008b, 2010; Walker et al, 2008)
Summary
The striatum receives input from all areas of cerebral cortex and uses that information to guide behavior. Cortical neurons are the primary driver of striatal neuronal activity. Striatal neurons are silent owing to an inwardly rectifying K+ current that keeps neuronal membranes hyperpolarized (Wilson and Kawaguchi, 1996). Glutamate released from cortical afferents increases striatal excitability, and when this input is coordinated across large numbers of afferents, the resulting activation of striatal circuits drives downstream processing through the rest of the basal ganglia (Wickens and Wilson, 1998). Autopsy of end-stage HD patients reveals substantial degeneration and loss of medium spiny neurons, which account for more than 90% of the striatal neuronal population (Groves, 1983). Medium spiny neurons are the sole output system of the striatum, and they receive massive glutamate input from cortical pyramidal cells, which undergo substantial degeneration and loss. Damage occurs in other brain regions, corticostriatal pathology appears to be the primary cause of the cognitive and motor abnormalities that characterize HD (Lawrence et al, 1998)
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