Mouse Models of Huntington’s Disease

Brooks, Simon Philip; Dunnett, Stephen B.

doi:10.1007/7854_2013_256

Cited by 23 publications

(18 citation statements)

References 252 publications

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“…However, these same synapses must be able to reverse this form of plasticity (ie, induction of LTD) to allow extinction or “forgetting” processes in response to new behavioral situations. Earlier genetic and pharmacological studies showed involvement of various striatal signaling molecules and circuits in behavioral flexibility …”

Section: Discussionmentioning

confidence: 99%

“…Earlier genetic and pharmacological studies showed involvement of various striatal signaling molecules and circuits in behavioral flexibility. 162,163 In this review, we pointed out that the emergence of abnormal activity pattern in striatal cholinergic interneurons that accompanied the dysfunction of striatal ACh signaling in BG disorders might contribute to pathological cortico-striatal synaptic plasticity. This abnormal cortico-striatal synaptic plasticity probably underlies some of the clinical disturbances in learning and switching behaviors seen in patients with BG disorders.…”

Section: Discussionmentioning

confidence: 99%

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Striatal cholinergic interneurons and cortico‐striatal synaptic plasticity in health and disease

Deffains¹,

Bergman²

2015

Movement Disorders

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Basal ganglia disorders such as Parkinson's disease, dystonia, and Huntington's disease are characterized by a dysregulation of the basal ganglia neuromodulators (dopamine, acetylcholine, and others), which impacts cortico-striatal transmission. Basal ganglia disorders are often associated with an imbalance between the midbrain dopaminergic and striatal cholinergic systems. In contrast to the extensive research and literature on the consequences of a malfunction of midbrain dopaminergic signaling on the plasticity of the cortico-striatal synapse, very little is known about the role of striatal cholinergic interneurons in normal and pathological control of cortico-striatal transmission. In this review, we address the functional role of striatal cholinergic interneurons, also known as tonically active neurons and attempt to understand how the alteration of their functional properties in basal ganglia disorders leads to abnormal cortico-striatal synaptic plasticity. Specifically, we suggest that striatal cholinergic interneurons provide a permissive signal, which enables long-term changes in the efficacy of the cortico-striatal synapse. We further discuss how modifications in the striatal cholinergic activity pattern alter or prohibit plastic changes of the cortico-striatal synapse. Long-term cortico-striatal synaptic plasticity is the cellular substrate of procedural learning and adaptive control behavior. Hence, abnormal changes in this plasticity may underlie the inability of patients with basal ganglia disorders to adjust their behavior to situational demands. Normalization of the cholinergic modulation of cortico-striatal synaptic plasticity may be considered as a critical feature in future treatments of basal ganglia disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Striatal cholinergic interneurons and cortico‐striatal synaptic plasticity in health and disease

Deffains¹,

Bergman²

2015

Movement Disorders

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“…A number of HD mouse models have been created over the years since the discovery of the causal mutation in the HTT gene. These models have been reviewed in detail elsewhere (Brooks and Dunnett, 2013;Pouladi et al, 2013), and here we will only highlight the ones that are most frequently used for the study of HD-related circuit defects ( Table 1). They can be divided into truncated and full-length models, the latter including transgenic and knock-in lines.…”

Section: Genetic Mouse Models Of Hdmentioning

confidence: 99%

Cortical and Striatal Circuits in Huntington’s Disease

Blumenstock

Dudanova

2020

Front. Neurosci.

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Huntington's disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

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“…For example, Huntington’s disease takes many years to evolve in humans, and to accelerate the process in mice, transgenics have been constructed that express much longer polyglutamine expansions than those appearing in nature. Perhaps as a result, none of the many types of nominally Huntington disease mice thus far developed faithfully replicate both the typical disease course and neuropathology of the disease in humans (Brooks and Dunnett, 2015; Howland and Munoz-Sanjuan, 2014; Menalled and Brunner, 2014). As such, whether cell therapeutic strategies modeled in these mice will prove as efficacious in HD patients remains an uncomfortable unknown.…”

Section: Hype: Limits To Therapeutic Advancementioning

confidence: 99%

Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking

2016

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A variety of neurological disorders are attractive targets for stem and progenitor cell-based therapy. Yet many conditions are not, whether by virtue of an inhospitable disease environment, poorly understood pathophysiology, or poor alignment of donor cell capabilities with patient needs. Moreover, some disorders may be medically feasible targets, but are not practicable, in light of already available treatments, poor risk-benefit and cost-benefit profiles, or resource limitations. This Perspective seeks to define those neurological conditions most appropriate for cell replacement therapy, by considering its potential efficacy and clinical feasibility in those disorders, as well as potential impediments to its application.

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Mouse Models of Huntington’s Disease

Cited by 23 publications

References 252 publications

Striatal cholinergic interneurons and cortico‐striatal synaptic plasticity in health and disease

Striatal cholinergic interneurons and cortico‐striatal synaptic plasticity in health and disease

Cortical and Striatal Circuits in Huntington’s Disease

Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking

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