Abstract
Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, impairs information processing in the striatum, which, as part of the basal ganglia, modulates motor output. Growing evidence suggests that huntingtin interacting protein 14 (HIP14) contributes to HD neuropathology. Here, we recorded local field potentials (LFPs) in the striatum as HIP14 knockout mice and wild-type controls freely navigated a plus-shaped maze. Upon entering the choice point of the maze, HIP14 knockouts tend to continue in a straight line, turning left or right significantly less often than wild-types, a sign of motor inflexibility that also occurs in HD mice. Striatal LFP activity anticipates this difference. In wild-types, the power spectral density pattern associated with entry into the choice point differs significantly from the pattern immediately before entry, especially at low frequencies (≤13 Hz), whereas HIP14 knockouts show no change in LFP activity as they enter the choice point. The lack of change in striatal activity may explain the turning deficit in the plus maze. Our results suggest that HIP14 plays a critical role in the aberrant behavioral modulation of striatal neuronal activity underlying motor inflexibility, including the motor signs of HD.
Highlights
Huntington’s disease (HD) is an inherited neurodegenerative disorder in which behavioral signs, mainly characterized by involuntary movements and cognitive decline, typically emerge in adulthood [1]
Among the changes induced by mutant huntingtin (mHTT) is a deficit in protein palmitoylation by huntingtin interacting protein 14 (HIP14), a palmitoyl acyl transferase (PAT) that binds palmitic acid [6,7,8]
Because evaluating patterns of arm choice provides information on behavioral flexibility, we focused our analysis of striatal local field potentials (LFPs) activity on events surrounding the choice point
Summary
Huntington’s disease (HD) is an inherited neurodegenerative disorder in which behavioral signs, mainly characterized by involuntary movements and cognitive decline, typically emerge in adulthood [1]. Failure to palmitoylate key proteins can impair synaptic transmission, which may account for the altered response of striatal neurons to cortical activation in HD mouse models [9]. At the choice point or center of the maze, these neurons, relative to those recorded from wild-type mice, change both the rate and pattern of spike activity. HIP14 in striatal function, suggest that aberrant striatal processing may underlie the motor inflexibility seen in HIP14 knockout mice. We extended this investigation to the population response of striatal neurons by analyzing local field potentials (LFPs) in conjunction with entering and exiting the choice point. A force-plate actometer monitored position in the maze and provided time-stamps for LFP activity
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