scholarly journals Striatal Potassium Channel Dysfunction in Huntington's Disease Transgenic Mice

2005 ◽  
Vol 93 (5) ◽  
pp. 2565-2574 ◽  
Author(s):  
Marjorie A. Ariano ◽  
Carlos Cepeda ◽  
Christopher R. Calvert ◽  
Jorge Flores-Hernández ◽  
Elizabeth Hernández-Echeagaray ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Projection Neurons ◽  
Electrophysiological Properties ◽  
Spiny Neurons ◽  
Subunit Expression ◽  
Dissociated Cells

Huntington's disease (HD) is a neurodegenerative disorder that mainly affects the projection neurons of the striatum and cerebral cortex. Genetic mouse models of HD have shown that neurons susceptible to the mutation exhibit morphological and electrophysiological dysfunctions before and during development of the behavioral phenotype. We used HD transgenic mouse models to examine inwardly and outwardly rectifying K+ conductances, as well as expression of some related K+ channel subunits. Experiments were conducted in slices and dissociated cells from two mouse models, the R6/2 and TgCAG100, at the beginning and after full development of overt behavioral phenotypes. Striatal medium-sized spiny neurons (MSNs) from symptomatic transgenic mice had increased input resistances, depolarized resting membrane potentials, and reductions in both inwardly and outwardly rectifying K+ currents. These changes were more dramatic in the R6/2 model than in the TgCAG100. Parallel immunofluorescence studies detected decreases in the expression of K+ channel subunit proteins, Kir2.1, Kir2.3, and Kv2.1 in MSNs, which contribute to the formation of the channel ionophores for these currents. Attenuation in K+ conductances and channel subunit expression contribute to altered electrophysiological properties of MSNs and may partially account for selective cellular vulnerability in the striatum.

scholarly journals Striatal Circuit Development and Its Alterations in Huntington’s Disease

2020 ◽  
Author(s):  
Margaux Lebouc ◽  
Quentin Richard ◽  
Maurice Garret ◽  
Jérôme Baufreton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Rodent Models ◽  
Network Development ◽  
Cag Repeat Expansion ◽  
Circuit Development

Huntington's disease (HD) is an inherited neurodegenerative disorder that usually starts during midlife with progressive alterations of motor and cognitive functions. The disease is caused by a CAG repeat expansion within the huntingtin gene leading to severe striatal neurodegeneration. Recent studies conducted on pre-HD children highlight early striatal developmental alterations starting as soon as 6 years old, the earliest age assessed. These findings, in line with data from mouse models of HD, raise the question of when during development do the first disease-related striatal alterations emerge or whether they contribute to the later appearance of the neurodegenerative features of the disease. In this review we will describe the different stages of striatal network development and then discuss recent evidence for its alterations in rodent models of the disease. We argue that a better understanding of the striatum’s development should help in assessing aberrant neurodevelopmental processes linked to the HD mutation.

scholarly journals Dysregulated Information Processing by Medium Spiny Neurons in Striatum of Freely Behaving Mouse Models of Huntington's Disease

2008 ◽  
Vol 100 (4) ◽  
pp. 2205-2216 ◽  
Author(s):  
Benjamin R. Miller ◽  
Adam G. Walker ◽  
Anand S. Shah ◽  
Scott J. Barton ◽  
George V. Rebec
Keyword(s):  
Information Processing ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Population Level ◽  
Medium Spiny Neurons ◽  
Processing Scheme ◽  
Background Strain ◽  
Spiny Neurons ◽  
Freely Behaving

Huntington's disease (HD) is an autosomal dominant condition that compromises behavioral output. Dysfunction of medium spiny neurons (MSNs), which are the sole output system of the striatum, is thought to underlie HD pathophysiology. What is not known is how HD alters MSN information processing during behavior, which likely drives the HD behavioral phenotype. We recorded from populations of MSNs in two freely behaving and symptomatic HD mouse models: R6/2 transgenics are based on a C57BL/6J*CBA/J background and show robust behavioral symptoms, whereas knock-in (KI) mice have a 129sv background and express relatively mild behavioral signs. At the single-unit level, we found that the MSN firing rate was elevated in R6/2 but not in KI mice compared with their respective wild-type (WT) controls. In contrast, burst activity, which corresponds to periods of high-frequency firing, was altered in both HD models compared with WT. At the population level, we found that correlated firing between pairs of MSNs was a prominent feature in WT that was reduced in both HD models. Similarly, coincident bursts, which are bursts between pairs of neurons that overlap in time and occur more often in pairs of MSNs that exhibit correlated firing, were decreased in HD mice. Our results indicate an important role in both bursting and correlated burst firing for information processing in MSNs. Dysregulation of this processing scheme, moreover, is a key component of HD pathophysiology regardless of the severity of HD symptoms, genetic construct, and background strain of the mouse models.

scholarly journals Enhanced GABAergic Inhibition of Cholinergic Interneurons in the zQ175+/− Mouse Model of Huntington's Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Sean Austin O. Lim ◽  
D. James Surmeier
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Ex Vivo ◽  
Brain Slices ◽  
Projection Neurons ◽  
Gabaergic Inhibition ◽  
Indirect Pathway ◽  
Cholinergic Interneurons ◽  
Specific Alteration

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that initially manifests itself in the striatum. How intrastriatal circuitry is altered by the disease is poorly understood. To help fill this gap, the circuitry linking spiny projection neurons (SPNs) to cholinergic interneurons (ChIs) was examined using electrophysiological and optogenetic approaches in ex vivo brain slices from wildtype mice and zQ175+/− models of HD. These studies revealed a severalfold enhancement of GABAergic inhibition of ChIs mediated by collaterals of indirect pathway SPNs (iSPNs), but not direct pathway SPNs (dSPNs). This cell-specific alteration in synaptic transmission appeared in parallel with the emergence of motor symptoms in the zQ175+/− model. The adaptation had a presynaptic locus, as it was accompanied by a reduction in paired-pulse ratio but not in the postsynaptic response to GABA. The alterations in striatal GABAergic signaling disrupted spontaneous ChI activity, potentially contributing to the network dysfunction underlying the hyperkinetic phase of HD.

scholarly journals Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases

2005 ◽  
Vol 169 (4) ◽  
pp. 647-656 ◽  
Author(s):  
Shouqing Luo ◽  
Coralie Vacher ◽  
Janet E. Davies ◽  
David C. Rubinsztein
Keyword(s):  
Amino Acids ◽  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cellular Membrane ◽  
Aggregate Formation ◽  
Polyq Tract ◽  
Polyq Expansion ◽  
In Cells

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) tract in the huntingtin (htt) protein. Mutant htt toxicity is exposed after htt cleavage by caspases and other proteases release NH2-terminal fragments containing the polyQ expansion. Here, we show htt interacts and colocalizes with cdk5 in cellular membrane fractions. Cdk5 phosphorylates htt at Ser434, and this phosphorylation reduces caspase-mediated htt cleavage at residue 513. Reduced mutant htt cleavage resulting from cdk5 phosphorylation attenuated aggregate formation and toxicity in cells expressing the NH2-terminal 588 amino acids (htt588) of mutant htt. Cdk5 activity is reduced in the brains of HD transgenic mice compared with controls. This result can be accounted for by the polyQ-expanded htt fragments reducing the interaction between cdk5 and its activator p35. These data predict that the ability of cdk5 phosphorylation to protect against htt cleavage, aggregation, and toxicity is compromised in cells expressing toxic fragments of htt.

scholarly journals Dysregulation of Neuronal Calcium Signaling via Store-Operated Channels in Huntington's Disease

2020 ◽  
Vol 8 ◽  
Author(s):  
Magdalena Czeredys
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transient Receptor Potential ◽  
Neurodegenerative Disorder ◽  
Induced Pluripotent Stem Cell ◽  
Receptor Potential ◽  
Medium Spiny Neurons ◽  
Trpc Channels ◽  
Polyglutamine Expansion ◽  
Spiny Neurons

Huntington's disease (HD) is a progressive neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric problems. It is caused by a polyglutamine expansion in the huntingtin protein that leads to striatal degeneration via the transcriptional dysregulation of several genes, including genes that are involved in the calcium (Ca2+) signalosome. Recent research has shown that one of the major Ca2+ signaling pathways, store-operated Ca2+ entry (SOCE), is significantly elevated in HD. SOCE refers to Ca2+ flow into cells in response to the depletion of endoplasmic reticulum Ca2+ stores. The dysregulation of Ca2+ homeostasis is postulated to be a cause of HD progression because the SOCE pathway is indirectly and abnormally activated by mutant huntingtin (HTT) in γ-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) from the striatum in HD models before the first symptoms of the disease appear. The present review summarizes recent studies that revealed a relationship between HD pathology and elevations of SOCE in different models of HD, including YAC128 mice (a transgenic model of HD), cellular HD models, and induced pluripotent stem cell (iPSC)-based GABAergic medium spiny neurons (MSNs) that are obtained from adult HD patient fibroblasts. SOCE in MSNs was shown to be mediated by currents through at least two different channel groups, Ca2+ release-activated Ca2+ current (ICRAC) and store-operated Ca2+ current (ISOC), which are composed of stromal interaction molecule (STIM) proteins and Orai or transient receptor potential channel (TRPC) channels. Their role under physiological and pathological conditions in HD are discussed. The role of Huntingtin-associated protein 1 isoform A in elevations of SOCE in HD MSNs and potential compounds that may stabilize elevations of SOCE in HD are also summarized. Evidence is presented that shows that the dysregulation of molecular components of SOCE or pathways upstream of SOCE in HD MSN neurons is a hallmark of HD, and these changes could lead to HD pathology, making them potential therapeutic targets.

scholarly journals Establishment and maintenance of an R6/1 transgenic mouse colony and validation of its progressive neurological phenotype to study Huntington’s disease

2018 ◽  
Vol 5 (1) ◽  
Author(s):  
Lucía Gabriela García-Lara ◽  
Adriana Morales-Martínez ◽  
Quetzalli Denisse Angeles-López ◽  
Hilda Pedraza-Espitia ◽  
Iván Pérez-Neri ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Transgenic Animal ◽  
Phenotypic Characteristics ◽  
Neurological Phenotype ◽  
Transgenic Animal Models ◽  
The Central Nervous System

Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the central nervous system that mainly affects the basal ganglia and has no cure. The mutation is located at an abnormal expansion of the CAG triplet in the Huntingtin gene. Humans show psychiatric, behavioural and motor disorders. Transgenic animal models are essential to the study of HD since the disease only affects humans. Therefore, the aim of this article was to describe the formation and maintenance of and to validate the progressive neurological phenotype of an R6/1 transgenic mouse colony. To achieve our objective, the colony founder was imported from Jackson Laboratories, and the mice were kept under controlled environmental conditions. The animals were bred at the vivarium of the Instituto Nacional de Neurología y Neurocirugía Man­uel Velasco Suárez. The R6/1 transgenic mice were successfully bred and showed genetic and phenotypic characteristics similar to the ones previously reported. Our colony is currently established and validated with the condi­tions of our vivarium and has produced more than four generations of R6/1 mice. The establishment of the R6/1 colony and its maintenance through generation is an advantage since it allows us to follow the authenticity of the transgenic mice regarding their phenotypic and motor behaviours. Fur­thermore, these animals can be compared with other transgenic mice that reproduce some of the main characteristics of the disease manifested in hu­mans, making these transgenic R6/1 mice a useful tool for the study of HD.

scholarly journals Rapid and robust patterns of spontaneous locomotor deficits in mouse models of Huntington’s disease

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243052
Author(s):  
Taneli Heikkinen ◽  
Timo Bragge ◽  
Niina Bhattarai ◽  
Teija Parkkari ◽  
Jukka Puoliväli ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Cag Repeats ◽  
Fine Motor ◽  
Waveform Data ◽  
Model Research ◽  
Locomotor Deficits ◽  
Locomotor Patterns

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by severe disruption of cognitive and motor functions, including changes in posture and gait. A number of HD mouse models have been engineered that display behavioral and neuropathological features of the disease, but gait alterations in these models are poorly characterized. Sensitive high-throughput tests of fine motor function and gait in mice might be informative in evaluating disease-modifying interventions. Here, we describe a hypothesis-free workflow that determines progressively changing locomotor patterns across 79 parameters in the R6/2 and Q175 mouse models of HD. R6/2 mice (120 CAG repeats) showed motor disturbances as early as at 4 weeks of age. Similar disturbances were observed in homozygous and heterozygous Q175 KI mice at 3 and 6 months of age, respectively. Interestingly, only the R6/2 mice developed forelimb ataxia. The principal components of the behavioral phenotypes produced two phenotypic scores of progressive postural instability based on kinematic parameters and trajectory waveform data, which were shared by both HD models. This approach adds to the available HD mouse model research toolbox and has a potential to facilitate the development of therapeutics for HD and other debilitating movement disorders with high unmet medical need.

scholarly journals The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kim Le Cann ◽  
Alec Foerster ◽  
Corinna Rösseler ◽  
Andelain Erickson ◽  
Petra Hautvast ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Induced Pluripotent Stem Cell ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Large Variability ◽  
Spiny Neurons ◽  
Induced Pluripotent

AbstractHuntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.

scholarly journals Cerebral Vitamin B5 (D-Pantothenic Acid) Deficiency as a Potential Cause of Metabolic Perturbation and Neurodegeneration in Huntington’s Disease

Metabolites ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 113 ◽  
Author(s):  
Stefano Patassini ◽  
Paul Begley ◽  
Jingshu Xu ◽  
Stephanie Church ◽  
Nina Kureishy ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Tricarboxylic Acid Cycle ◽  
Pantothenic Acid ◽  
Polyol Pathway ◽  
Brain Regions ◽  
Cag Repeat ◽  
Projection Neurons ◽  
Vitamin B5

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the HTT gene. HD usually manifests in mid-life with loss of GABAergic projection neurons from the striatum accompanied by progressive atrophy of the putamen followed by other brain regions, but linkages between the genetics and neurodegeneration are not understood. We measured metabolic perturbations in HD-human brain in a case-control study, identifying pervasive lowering of vitamin B5, the obligatory precursor of coenzyme A (CoA) that is essential for normal intermediary metabolism. Cerebral pantothenate deficiency is a newly-identified metabolic defect in human HD that could potentially: (i) impair neuronal CoA biosynthesis; (ii) stimulate polyol-pathway activity; (iii) impair glycolysis and tricarboxylic acid cycle activity; and (iv) modify brain-urea metabolism. Pantothenate deficiency could lead to neurodegeneration/dementia in HD that might be preventable by treatment with vitamin B5.

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