Striatal Network Models of Huntington's Disease Dysfunction Phenotypes

Zheng, Pengsheng; Kozloski, James

doi:10.3389/fncom.2017.00070

Cited by 16 publications

(13 citation statements)

References 35 publications

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“…Future modeling work to predict intrinsic mechanisms that underlie firing properties in each of these four groups will help elucidate interactions between morphology and ion channel dysregulation in MSNs in mouse models of HD. Such findings will complement recent modeling studies of the effects of HD on network-level function in the striatal microcircuit [ 69 , 70 ].…”

Section: Discussionsupporting

confidence: 60%

Differential changes to D1 and D2 medium spiny neurons in the 12-month-old Q175+/- mouse model of Huntington’s Disease

et al. 2018

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Huntington’s Disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by deleterious expansion of CAG repeats in the Huntingtin gene and production of neurotoxic mutant Huntingtin protein (mHTT). The key pathological feature of HD is a profound degeneration of the striatum and a loss of cortical volume. The initial loss of indirect pathway (D2) medium spiny neuron (MSN) projections in early stages of HD, followed by a loss of direct pathway (D1) projections in advanced stages has important implications for the trajectory of motor and cognitive dysfunction in HD, but is not yet understood. Mouse models of HD have yielded important information on the effects and mechanisms of mHTT toxicity; however, whether these models recapitulate differential vulnerability of D1 vs. D2 MSNs is unknown. Here, we employed 12-month-old Q175+/- x D2-eGFP mice to examine the detailed structural and functional properties of D1 vs. D2 MSNs. While both D1 and D2 MSNs exhibited increased input resistance, depolarized resting membrane potentials and action potential threshold, only D1 MSNs showed reduced rheobase, action potential amplitude and frequency of spontaneous excitatory postsynaptic currents. Furthermore, D1 but not D2 MSNs showed marked proliferative changes to their dendritic arbors and reductions in spine density. Immunohistochemical assessment showed no loss of glutamatergic afferent inputs from cortical and subcortical sources onto identified D1 and D2 MSNs. Computational models constrained by empirical data predict that the increased dendritic complexity in Q175+/- D1 MSNs likely leads to greater dendritic filtering and attenuation of signals propagating to the soma from the dendrites. Together these findings reveal that, by twelve months, D1 and D2 MSNs exhibit distinctive responses to the presence of mHTT in this important mouse model of HD. This further highlights the need to incorporate findings from D1 and D2 MSNs independently in the context of HD models.

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Section: Discussionsupporting

confidence: 60%

Differential changes to D1 and D2 medium spiny neurons in the 12-month-old Q175+/- mouse model of Huntington’s Disease

et al. 2018

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“…Progressive MSN cell death is well established however, and in some agreement with our results, would manifest as a gradual reduction in our parameter g I at advancing symptomatic ages, as would the general reduction in MSN-MSN connection probability found in [10]. Our model assumes a random network; asymmetric connectivity patterns [10,152] and spatial distortions of dendritic trees [153][154][155] found in HD should be investigated in future modeling.…”

Section: Plos Computational Biologysupporting

confidence: 81%

Striatal network modeling in Huntington’s Disease

et al. 2020

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Medium spiny neurons (MSNs) comprise over 90% of cells in the striatum. In vivo MSNs display coherent burst firing cell assembly activity patterns, even though isolated MSNs do not burst fire intrinsically. This activity is important for the learning and execution of action sequences and is characteristically dysregulated in Huntington's Disease (HD). However, how dysregulation is caused by the various neural pathologies affecting MSNs in HD is unknown. Previous modeling work using simple cell models has shown that cell assembly activity patterns can emerge as a result of MSN inhibitory network interactions. Here, by directly estimating MSN network model parameters from single unit spiking data, we show that a network composed of much more physiologically detailed MSNs provides an excellent quantitative fit to wild type (WT) mouse spiking data, but only when network parameters are appropriate for the striatum. We find the WT MSN network is situated in a regime close to a transition from stable to strongly fluctuating network dynamics. This regime facilitates the generation of low-dimensional slowly varying coherent activity patterns and confers high sensitivity to variations in cortical driving. By re-estimating the model on HD spiking data we discover network parameter modifications are consistent across three very different types of HD mutant mouse models (YAC128, Q175, R6/2). In striking agreement with the known pathophysiology we find feedforward excitatory drive is reduced in HD compared to WT mice, while recurrent inhibition also shows phenotype dependency. We show that these modifications shift the HD MSN network to a sub-optimal regime where higher dimensional incoherent rapidly fluctuating activity predominates. Our results provide insight into a diverse range of experimental findings in HD, including cognitive and motor symptoms, and may suggest new avenues for treatment.

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“…This suggests that Htt may play a role in proper CNS development by ensuring proper motor skill development and coordination through the facilitation of progenitor cell polarity and differentiation during neurogenesis. The striatum, being the input model for the basal ganglia, emits signals to dictate learning through action selection and behavior reinforcement [13,25,26]. Classified as a basal ganglia disease, HD phenotypes are typically subtle, with a slow progression, until the patient is unable to move and speak [20].…”

Section: Figurementioning

confidence: 99%

Intersection of Redox Chemistry and Ubiquitylation: Post-Translational Modifications Required for Maintaining Cellular Homeostasis and Neuroprotection

Kane

Waters

Spratt

2021

Cells

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Neurodegeneration has been predominantly recognized as neuronal breakdown induced by the accumulation of aggregated and/or misfolded proteins and remains a preliminary factor in age-dependent disease. Recently, critical regulating molecular mechanisms and cellular pathways have been shown to induce neurodegeneration long before aggregate accumulation could occur. Although this opens the possibility of identifying biomarkers for early onset diagnosis, many of these pathways vary in their modes of dysfunction while presenting similar clinical phenotypes. With selectivity remaining difficult, it is promising that these neuroprotective pathways are regulated through the ubiquitin-proteasome system (UPS). This essential post-translational modification (PTM) involves the specific attachment of ubiquitin onto a substrate, specifically marking the ubiquitin-tagged protein for its intracellular fate based upon the site of attachment, the ubiquitin chain type built, and isopeptide linkages between different ubiquitin moieties. This review highlights both the direct and indirect impact ubiquitylation has in oxidative stress response and neuroprotection, and how irregularities in these intricate processes lead towards the onset of neurodegenerative disease (NDD).

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Striatal Network Models of Huntington's Disease Dysfunction Phenotypes

Cited by 16 publications

References 35 publications

Differential changes to D1 and D2 medium spiny neurons in the 12-month-old Q175+/- mouse model of Huntington’s Disease

Differential changes to D1 and D2 medium spiny neurons in the 12-month-old Q175+/- mouse model of Huntington’s Disease

Striatal network modeling in Huntington’s Disease

Intersection of Redox Chemistry and Ubiquitylation: Post-Translational Modifications Required for Maintaining Cellular Homeostasis and Neuroprotection

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