Calcium dysregulation and compensation in cortical pyramidal neurons of the R6/2 mouse model of Huntington’s disease

2021 ◽  
Vol 126 (4) ◽  
pp. 1159-1171
Author(s):  
Katerina D. Oikonomou ◽  
Elissa J. Donzis ◽  
Minh T. N. Bui ◽  
Carlos Cepeda ◽  
Michael S. Levine
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pyramidal Neurons ◽  
Calcium Influx ◽  
Calcium Transient ◽  
Two Photon Microscopy ◽  
Decay Times ◽  
Cortical Pyramidal Neurons ◽  
Receptor Blockers

We used two-photon microscopy to examine calcium influx induced by action potentials in cortical pyramidal neurons from a mouse model of Huntington’s disease (HD), the R6/2. The amplitude of somatic calcium transients was reduced in R6/2 mice compared with controls. This reduction was compensated by increased decay times, which could lead to reduced calcium buffering capacity. L-type calcium channel and ryanodine receptor blockers reduced calcium transient area in HD neurons, suggesting new therapeutic avenues.

scholarly journals Altered excitatory and inhibitory inputs to striatal medium-sized spiny neurons and cortical pyramidal neurons in the Q175 mouse model of Huntington's disease

2015 ◽  
Vol 113 (7) ◽  
pp. 2953-2966 ◽  
Author(s):  
Tim Indersmitten ◽  
Conny H. Tran ◽  
Carlos Cepeda ◽  
Michael S. Levine
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Primary Motor Cortex ◽  
Pyramidal Neurons ◽  
Membrane Properties ◽  
Postsynaptic Currents ◽  
Spiny Neurons ◽  
Cortical Pyramidal Neurons ◽  
Intrinsic Membrane Properties

The Q175 knockin mouse model of Huntington's disease (HD) carries a CAG trinucleotide expansion of the human mutant huntingtin allele in its native mouse genomic context and recapitulates the genotype more closely than transgenic models. In this study we examined the progression of changes in intrinsic membrane properties and excitatory and inhibitory synaptic transmission, using whole cell patch-clamp recordings of medium-sized spiny neurons (MSNs) in the dorsolateral striatum and cortical pyramidal neurons (CPNs) in layers 2/3 of the primary motor cortex in brain slices from heterozygous (Q175+/−) and homozygous (Q175+/+) mice. Input resistance in MSNs from Q175+/+ and Q175+/− mice was significantly increased compared with wild-type (WT) littermates beginning at 2 mo. Furthermore, the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was significantly reduced in MSNs from Q175+/+ and Q175+/− mice compared with WTs beginning at 7 mo. In contrast, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and IPSC-to-EPSC ratios were increased in MSNs from Q175+/+ mice beginning at 2 mo. Morphologically, significant decreases in spine density of MSNs from Q175+/− and Q175+/+ mice occurred at 7 and 12 mo. In CPNs, sIPSC frequencies and IPSC-to-EPSC ratios were significantly increased in Q175+/− mice compared with WTs at 12 mo. There were no changes in intrinsic membrane properties or morphology. In summary, we show a number of alterations in electrophysiological and morphological properties of MSNs in Q175 mice that are similar to other HD mouse models. However, unlike other models, CPN inhibitory activity is increased in Q175+/− mice, indicating reduced cortical excitability.

Altered Cortical Glutamate Receptor Function in the R6/2 Model of Huntington's Disease

2006 ◽  
Vol 95 (4) ◽  
pp. 2108-2119 ◽  
Author(s):  
Véronique M. André ◽  
Carlos Cepeda ◽  
Angela Venegas ◽  
Yeranui Gomez ◽  
Michael S. Levine
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Glutamate Receptor ◽  
Pyramidal Neurons ◽  
Splice Variants ◽  
Cag Repeats ◽  
Receptor Function ◽  
Motor Impairments ◽  
Cortical Pyramidal Neurons ◽  
Exon 1

Alterations in pyramidal neurons from the sensorimotor cortex may be responsible for some of the cognitive and motor symptoms of Huntington's disease (HD). The present experiments used R6/2 transgenic mice that express exon 1 of the human HD gene with an expanded number of CAG repeats. We characterized α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents and their modulation by cyclothiazide (CTZ) as well as N-methyl-d-aspartate (NMDA) currents and their Mg2+ sensitivity in acutely dissociated cortical pyramidal neurons in R6/2 transgenic and wild-type (WT) mice at 21 days (before overt symptoms), 40 days (when symptoms begin), and 80 days (fully symptomatic). AMPA currents, alone or in the presence of CTZ, were smaller in 21- and 40-day-old R6/2 groups compared with WT mice. In R6/2 mice, more neurons displayed desensitizing AMPA currents in the presence of CTZ, indicating increased expression of “flop” splice variants, whereas the majority of WT cells expressed the “flip” variants of AMPA receptor subunits. NMDA peak currents also were smaller in R6/2 pyramidal neurons at 21 days. At 40 days, NMDA currents were similar in WT and R6/2 mice but Mg2+ sensitivity was greater in R6/2 mice, resulting in smaller NMDA currents in the presence of Mg2+. Differences in AMPA and NMDA currents between WT and R6/2 cells were no longer detected at 80 days. Our findings indicate that currents induced by glutamate receptor agonists are decreased in isolated cortical pyramidal neurons from R6/2 mice and that this decrease occurs early. Altered glutamate receptor function could contribute to changes in cortical output and may underlie some of the cognitive and motor impairments in this animal model of HD.

scholarly journals Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington’s Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

2021 ◽  
Author(s):  
Danielle A. Simmons ◽  
Brian D. Mills ◽  
Robert R. Butler III ◽  
Jason Kuan ◽  
Tyne L. M. McHugh ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Treatment Response ◽  
Diffusion Tensor ◽  
Disease Onset ◽  
Therapeutic Effects ◽  
Plasma Cytokine ◽  
Cytokine Levels ◽  
Pharmacodynamic Biomarkers

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

Plasma inflammatory biomarkers for Huntington’s disease patients and mouse model

2015 ◽  
Vol 44 ◽  
pp. 121-127 ◽  
Author(s):  
Kuo-Hsuan Chang ◽  
Yih-Ru Wu ◽  
Yi-Chun Chen ◽  
Chiung-Mei Chen
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Inflammatory Biomarkers
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