TY - JOUR T1 - Cortico-striatal cross-frequency coupling and gamma genesis disruptions in Huntington’s disease mouse and computational models JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0210-18.2018 SP - ENEURO.0210-18.2018 AU - Sebastien Naze AU - James Humble AU - Pengsheng Zheng AU - Scott Barton AU - Claudia Rangel-Barajas AU - George V. Rebec AU - James R. Kozloski Y1 - 2018/11/29 UR - http://www.eneuro.org/content/early/2018/11/29/ENEURO.0210-18.2018.abstract N2 - Abnormal gamma band power across cortex and striatum is an important phenotype of Huntington's disease (HD) in both patients and animal models, but neither the origin nor the functional relevance of this phenotype is well understood. Here, we analyzed local field potential (LFP) activity in freely behaving, symptomatic R6/2 and Q175 mouse models and corresponding wild-type (WT) controls. We focused on periods of quiet rest, which show strong gamma activity in HD mice. Simultaneous recording from motor cortex and its target area in dorsal striatum in the R6/2 model revealed exaggerated functional coupling over that observed in WT between the phase of delta frequencies (1-4 Hz) in cortex and striatum and striatal amplitude modulation of low gamma frequencies (25-55 Hz) (i.e. “phase amplitude coupling”), but no evidence that abnormal cortical activity alone can account for the increase in striatal gamma power. Both HD mouse models had stronger coupling of gamma amplitude to delta phase and more uni-modal phase distributions than their WT counterparts. To assess the possible role of striatal fast-spiking interneurons (FSIs) in these phenomena, we developed a computational model based on additional striatal recordings from Q175 mice. Changes in peak gamma frequency and power ratio were readily reproduced by our computational model, accounting for several experimental findings reported in the literature. Our results suggest that HD is characterized by both a reorganization of cortico-striatal drive and specific population changes related to intra-striatal synaptic coupling.Significance statement In HD, functional impairments first impact movement (chorea, dyskinesia) and cognition (executive functions, abstract thinking). Neuronal dysfunction associated with deficits appear first in cerebral cortex and striatum, which displays abnormally strong power in the low gamma band (25-55 Hz). Fast-spiking interneurons (FSIs) are a neuronal subtype putatively capable of forming networks that resonate at the gamma frequency. Here we show that FSI networks can implement an early routing bias for more abundant neuronal subtypes in striatum. Specifically, by analyzing in vivo electrophysiological recordings from HD mice at rest when gamma is strong and using computational modeling, we identify coupling changes between cortex and striatum sufficient to generate periods of abnormal FSI network gamma in response to slow wave cortical inputs. ER -