Cortical circuit alterations precede motor impairments in Huntington’s disease mice

Abstract

Huntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a time-resolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD.

Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

“…Correlated activity argues against cell autonomously elevated activity levels of individual cells but rather point to circuit mechanisms (such as increased synaptic inputs or a lack of inhibition). Interestingly, similar alterations within cortex were also recently described in other mouse models of neurodegenerative diseases (NDs), such as Huntington's disease 37 , potentially indicating that impaired E/I balance constitutes a general feature in NDs. Previous work has reported epileptic discharges in APP transgenic mice primarily seen during low gamma states, which the authors linked to impaired function of particularly parvalbumin (PV) positive interneurons 22 .…”

Motor Learning Promotes Remyelination via New and Surviving Oligodendrocytes

“…Hyperexcitability, and subsequent behavioral impairment, could be due to alterations in the myelination of thalamocortical input, corticospinal output axons, or of local circuitry within primary motor cortex. In neurodegenerative disorders, local circuit processing alterations produce hyperexcitability [58][59][60] , which predicts imminent motor impairments in both human patients and animal models 61,62,63 .…”

Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations

“…Consistent with this idea, electrophysiological studies in the BACHD mouse model (Gray et al, ) found decreased layer II/III PV‐interneuron excitation and decreased CPN inhibition at 6 months, when behavioral symptoms become evident (Gu et al, ; Spampanato, Gu, Yang, & Mody, ). Interestingly, it was recently shown that R6/2 mice have fewer perisomatic PV‐positive terminals on CPNs than their wild type (WT) counterparts, an observation that was also consistent in HD autopsy brains (Burgold et al, ). Importantly, this reduced inhibition was reflected by increased cortical activity measured with in vivo calcium imaging.…”