Genetic Mouse Models of Huntington's Disease: Focus on Electrophysiological Mechanisms

Cepeda, Carlos; Cummings, Damian M.; André, Véronique; Holley, Sandra M.; Levine, Michael S.

doi:10.1042/an20090058

Cited by 80 publications

(66 citation statements)

References 125 publications

(158 reference statements)

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“…The electrophysiological data did not show any decrease of EPSCs in the D9-N171-98Q mice suggesting that glutamate synaptic transmission is not altered in mice in which polyQ-htt expression is restricted to MSNs. IPSCs were not changed either, again in contrast to other studies showing an increase of GABA synaptic activity in several models of HD [79]. Thus, corticostriatal disconnection may not develop in symptomatic D9-N171-98Q mice.…”

Section: )contrasting

confidence: 51%

“…Importantly, the abnormalities evolve as the mouse goes from pre-symptomatic to symptomatic. MSNs from pre-symptomatic mice display increased excitatory postsynaptic currents (EPSCs), whereas MSNs from symptomatic mice display decreased EPSCs [79]. Neurophysiologic abnormalities also exist in cortical neurons, although in the opposite direction as in MSNs.…”

Section: )mentioning

confidence: 99%

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Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

120

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Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

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Section: )contrasting

confidence: 51%

Section: )mentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

120

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“…The drop in CB1 receptor expression in HD patients (49) and HD models (50-52) could be a compensation in response to elevated D 2 receptor signaling in HD: LTD in iSPN is mediated by presynaptic CB1 receptors activated by postsynaptically generated endocannabinoids (53). Deficits in striatal glutamatergic synaptic transmission have been seen in HD models, particularly at ages at which symptoms are evident (54). However, much remains to be done to tie these deficits to mechanisms that could be therapeutically manipulated.…”

Section: Hd Pathogenesis Is Rooted In Network Dysfunctionmentioning

confidence: 99%

“…There is evidence of elevated calpain activity in the striatum of YAC128 mice, perhaps due to a greater propensity for SPNs in HD mice to elevate dendritic Ca 2+ concentration in response to synaptic activity. This could happen in a number of ways; for example, there could be greater synchrony in cortical or thalamic activity, leading to stronger engagement of NMDARs (54). A relevant and poorly understood feature of SPNs in this regard is their cycling between down-states and up-states (62).…”

Section: Hd Pathogenesis Is Rooted In Network Dysfunctionmentioning

confidence: 99%

Brain networks in Huntington disease

Eidelberg¹,

Surmeier²

2011

J. Clin. Invest.

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Recent studies have focused on understanding the neural mechanisms underlying the emergence of clinical signs and symptoms in early stage Huntington disease (HD). Although cell-based assays have focused on cell autonomous effects of mutant huntingtin, animal HD models have revealed alterations in the function of neuronal networks, particularly those linking the cerebral cortex and striatum. These findings are complemented by metabolic imaging studies of disease progression in premanifest subjects. Quantifying metabolic progression at the systems level may identify network biomarkers to aid in the objective assessment of new disease-modifying therapies and identify new regions that merit mechanistic study in HD models. Neuropathology in Huntington diseaseHuntington disease (HD) is caused by expansion of a CAG repeat in the huntingtin (Htt) gene. Expansion of the repeat length beyond 35 CAGs significantly elevates disease risk (1). The Htt gene is ubiquitously expressed in the brain with relative enrichment in cortical pyramidal neurons projecting to the striatum but relatively low levels in striatal projection neurons (2, 3).Although there are clear effects in the cerebral cortex and hippocampus, the most pronounced neuropathology in HD is found in the striatum (4, 5). The striatum is a key component of the basal ganglia, an interconnected set of subcortical nuclei involved in the regulation of how to act (and not act) in particular contexts (6). The striatum is composed primarily of GABAergic projection neurons with dendrites that are heavily studded with spines. These spiny projection neurons (SPNs) can be subdivided into two major classes on the basis of their axonal projection, dendritic size, and physiology as well as their expression of dopamine receptors and releasable peptides (7,8). SPNs that project to the external segment of the globus pallidus (GPe) form what is called the indirect SPN (iSPN) pathway because they indirectly control the nuclei that interface between the basal ganglia and the rest of the brain. SPNs that project to the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata form the direct SPN (dSPN) pathway. iSPNs are smaller and more excitable than dSPNs (Figure 1 and ref. 9); this difference is very likely to reflect a tonic negative modulation of iSPNs by dopamine acting at D 2 receptors. In contrast, dSPNs are positively modulated by D 1 receptors that appear to only be activated by transient elevations in dopamine release produced by bursts of action potentials in dopaminergic neurons (10).iSPNs and dSPNs are generally thought to play complementary roles in movement control and action selection. Both SPN populations have a rich, highly convergent synaptic connectivity with glutamatergic neurons distributed throughout much of the cerebral cortex (11). Both populations also have rich connectivity with glutamatergic neurons in the thalamus (12). A broad array of experimental evidence supports the proposition that iSPNs help to suppress cortical selection of...

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“…Like cortical neurons, striatal MSN electrophysiology is altered in HD models, and again in vitro data point to an increase in neuronal excitability (19,65,70,87). Intracellular recordings from R6/2 and knock-in mice, for example, indicate that MSNs have a depolarized resting membrane potential and enhanced sensitivity of the NMDA glutamate receptor relative to wild-type (18,71).…”

Section: Altered Corticostriatal Processingmentioning

confidence: 99%

Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease

Rebec

2013

Antioxidants & Redox Signaling

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Significance: Dysregulation of cortical and striatal neuronal processing plays a critical role in Huntington's disease (HD), a dominantly inherited condition that includes a progressive deterioration of cognitive and motor control. Growing evidence indicates that ascorbate (AA), an antioxidant vitamin, is released into striatal extracellular fluid when glutamate is cleared after its release from cortical afferents. Both AA release and glutamate uptake are impaired in the striatum of transgenic mouse models of HD owing to a downregulation of glutamate transporter 1 (GLT1), the protein primarily found on astrocytes and responsible for removing most extracellular glutamate. Improved understanding of an AA-glutamate interaction could lead to new therapeutic strategies for HD. Recent Advances: Increased expression of GLT1 following treatment with ceftriaxone, a beta-lactam antibiotic, increases striatal glutamate uptake and AA release and also improves the HD behavioral phenotype. In fact, treatment with AA alone restores striatal extracellular AA to wild-type levels in HD mice and not only improves behavior but also improves the firing pattern of neurons in HD striatum. Critical Issues: Although evidence is growing for an AA-glutamate interaction, several key issues require clarification: the site of action of AA on striatal neurons; the precise role of GLT1 in striatal AA release; and the mechanism by which HD interferes with this role. Future Directions: Further assessment of how the HD mutation alters corticostriatal signaling is an important next step. A critical focus is the role of astrocytes, which express GLT1 and may be the primary source of extracellular AA.

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Genetic Mouse Models of Huntington's Disease: Focus on Electrophysiological Mechanisms

Cited by 80 publications

References 125 publications

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Brain networks in Huntington disease

Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease

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