Transgenic Model Of Huntington's Disease Research Articles

The pathobiology of depression in Huntington's disease: an unresolved puzzle.

Huntington's disease (HD) is an autosomal-dominant progressive neurodegenerative disease that manifests with a triad of symptoms including motor dysfunctions, cognitive deficits, and prominent neuropsychiatric symptoms, the most common of which is depression, with a prevalence between 30 and 70%. Depressive symptoms occur in all stages of HD, beginning in presymptomatic HD gene carriers, and are strongly associated with suicidal ideation and suicidality, but their relationship with other clinical dimensions in HD is controversial and the underlying pathophysiology is poorly understood. Analysis of the available literature until November 2023 concerned the prevalence, clinical manifestations, neuroimaging, transgenic models, and treatment options of HD depression. While it was believed that depression in HD is due to psychosomatic factors in view of the fatal disease, studies in transgenic models of HD demonstrated molecular changes including neurotrophic and serotonergic dysregulation and disorders of the hypothalamic-pituitary-adrenal axis inducing depression-like changes. While relevant neuropathological data are missing, recent neuroimaging studies revealed correlations between depressive symptoms and dysfunctional connectivities in the default mode network, basal ganglia and prefrontal cortex, and changes in limbic and paralimbic structures related to the basic neurodegenerative process. The impact of response to antidepressants in HD patients is controversial; selective serotonin reuptake inhibitors are superior to serotonin-norepinephrine reuptake inhibitors, while electroconvulsive therapy may be effective for pharmacotherapy resistant cases. Since compared to major depressive disorder and depression in other neurodegenerative diseases, our knowledge of the molecular basis in HD depression is limited, further studies to elucidate the heterogeneous pathogenesis in this fatal disorder are warranted.

Fullerenols Prevent Neuron Death and Reduce Oxidative Stress in Drosophila Huntington's Disease Model.

Huntington's disease (HD) is one of the human neurodegenerative diseases for which there is no effective treatment. Therefore, there is a strong demand for a novel neuroprotective agent that can alleviate its course. Fullerene derivatives are considered to be such agents; however, they need to be comprehensively investigated in model organisms. In this work, neuroprotective activity of C60(OH)30 and C120O(OH)44 fullerenols was analyzed for the first time in a Drosophila transgenic model of HD. Lifespan, behavior, oxidative stress level and age-related neurodegeneration were assessed in flies with the pathogenic Huntingtin protein expression in nerve cells. Feed supplementation with hydroxylated C60 fullerene and C120O dimer oxide molecules was shown to diminish the oxidative stress level and neurodegenerative processes in the flies' brains. Thus, fullerenes displayed neuroprotective activity in this model.

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

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.

Striatal infusion of cholesterol promotes dose-dependent behavioral benefits and exerts disease-modifying effects in Huntington's disease mice.

A variety of pathophysiological mechanisms are implicated in Huntington's disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre‐symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol‐loaded brain‐permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini‐pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and rate‐controlled manner. All tested doses prevented cognitive decline, while amelioration of disease‐related motor defects was dose‐dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose‐dependent, disease‐modifying effect and may be therapeutically relevant in HD.

Age-related alteration of emotional regulation in the BACHD rat model of Huntington disease.

Huntington's disease (HD) is a genetic neurodegenerative disorder, caused by an expanded CAG repeat in the gene encoding the huntingtin protein. At the premanifest phase, before motor symptoms occur, psychiatric and emotional disorders are observed with high prevalence in HD patients. Agitation, anxiety and irritability are often described but also depression and/or apathy, associated with a lack of emotional control. The aim of the present study was to better circumscribe and understand the emotional symptoms and assess their evolution according to the progression of the disease using a transgenic HD model, BACHD rats, at the age of 4, 12 and 18 months. To achieve this goal, we confronted animals to two types of tests: first, tests assessing anxiety like the light/dark box and the conflict test, which are situations that did not involve an obvious threat and tests assessing the reactivity to a present threat using confrontation with an unknown conspecific (social behavior test) or with an aversive stimulus (fear conditioning test). In all animals, results show an age-dependent anxiety-like behavior, particularly marked in situation requiring passive responses (light/dark box and fear conditioning tests). BACHD rats exhibited a more profound alteration than WT animals in these tests from an early stage of the disease whereas, in tasks requiring some kind of motivation (for food or for social contacts), only old BACHD rats showed high anxiety-like behavior compared to WT, may be partly due to the other symptoms' occurrence at this stage: locomotor difficulties and/or apathy.

Selenium Nanoparticles as an Efficient Nanomedicine for the Therapy of Huntington's Disease.

Huntington's disease (HD) is an incurable disease with progressive loss of neural function, which is influenced by epigenetic, oxidative stress, metabolic, and nutritional factors. Targeting inhibition of huntingtin protein aggregation is a strategy for HD therapy, but the efficacy is unsatisfactory. Studies found that selenium (Se) levels in the brain are insufficient for HD disease individuals, while improvement in Se homeostasis in the brain may attenuate neuronal loss and dysfunction. In this study, we applied selenium nanoparticles (NPs) (Nano-Se) for the HD disease therapy by regulating HD-related neurodegeneration and cognitive decline based on transgenic HD models of Caenorhabditis elegans (C. elegans). At low dosages, Nano-Se NPs significantly reduced neuronal death, relieved behavioral dysfunction, and protected C. elegans from damages in stress conditions. The molecular mechanism further revealed that Nano-Se attenuated oxidative stress, inhibited the aggregation of huntingtin proteins, and downregulated the expression of histone deacetylase family members at mRNA levels. The results suggested that Nano-Se has great potential for Huntington's disease therapy. In conclusion, the mechanism about how Nano-Se NPs protect from damages in stress conditions and how they repair neural functions will benefit HD disease therapy. This study will also guide rational design of Nano-Se NPs or other selenium compounds to improve HD therapy in the future.

Huntingtin-Associated Protein 1A Regulates Store-Operated Calcium Entry in Medium Spiny Neurons From Transgenic YAC128 Mice, a Model of Huntington's Disease.

Huntington’s disease (HD) is a hereditary neurodegenerative disease that is caused by polyglutamine expansion within the huntingtin (HTT) gene. One of the cellular activities that is dysregulated in HD is store-operated calcium entry (SOCE), a process by which Ca2+ release from the endoplasmic reticulum (ER) induces Ca2+ influx from the extracellular space. HTT-associated protein-1 (HAP1) is a binding partner of HTT. The aim of the present study was to examine the role of HAP1A protein in regulating SOCE in YAC128 mice, a transgenic model of HD. After Ca2+ depletion from the ER by the activation of inositol-(1,4,5)triphosphate receptor type 1 (IP3R1), we detected an increase in the activity of SOC channels when HAP1 protein isoform HAP1A was overexpressed in medium spiny neurons (MSNs) from YAC128 mice. A decrease in the activity of SOC channels in YAC128 MSNs was observed when HAP1 protein was silenced. In YAC128 MSNs that overexpressed HAP1A, an increase in activity of IP3R1 was detected while the ionomycin-sensitive ER Ca2+ pool decreased. 6-Bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (C20H22BrClN2), identified in our previous studies as a SOCE inhibitor, restored the elevation of SOCE in YAC128 MSN cultures that overexpressed HAP1A. The IP3 sponge also restored the elevation of SOCE and increased the release of Ca2+ from the ER in YAC128 MSN cultures that overexpressed HAP1A. The overexpression of HAP1A in the human neuroblastoma cell line SK-N-SH (i.e., a cellular model of HD (SK-N-SH HTT138Q)) led to the appearance of a pool of constitutively active SOC channels and an increase in the expression of STIM2 protein. Our results showed that HAP1A causes the activation of SOC channels in HD models by affecting IP3R1 activity.

The Effect of Tissue Preparation and Donor Age on Striatal Graft Morphology in the Mouse

Huntington's disease (HD) is a progressive neurodegenerative disease in which striatal medium spiny neurons (MSNs) are lost. Neuronal replacement therapies aim to replace MSNs through striatal transplantation of donor MSN progenitors, which successfully improve HD-like deficits in rat HD models and have provided functional improvement in patients. Transplants in mouse models of HD are more variable and have lower cell survival than equivalent rat grafts, yet mice constitute the majority of transgenic HD models. Improving the quality and consistency of mouse transplants would open up access to this wider range of rodent models and facilitate research to increase understanding of graft mechanisms, which is essential to progress transplantation as a therapy for HD. Here we determined how donor age, cell preparation, and donor/host strain choice influenced the quality of primary embryonic grafts in quinolinic acid lesion mouse models of HD. Both a within-strain (W-S) and a between-strain (B-S) donor/host paradigm were used to compare transplants of donor tissues derived from mice at embryonic day E12 and E14 prepared either as dissociated suspensions or as minimally manipulated tissue pieces (TP). Good graft survival was observed, although graft volume and cellular composition were highly variable. The effect of cell preparation on grafts differed significantly depending on donor age, with E14 cell suspensions yielding larger grafts compared to TP. Conversely, TP were more effective when derived from E12 donor tissue. A W-S model produced larger grafts with greater MSN content, and while high levels of activated microglia were observed across all groups, a greater number was found in B-S transplants. In summary, we show that the effect of tissue preparation on graft morphology is contingent on the age of donor tissue used. The presence of microglial activation in all groups highlights the host immune response as an important consideration in mouse transplantation.

Effects of a Sativex-Like Combination of Phytocannabinoids on Disease Progression in R6/2 Mice, an Experimental Model of Huntington's Disease.

Several cannabinoids afforded neuroprotection in experimental models of Huntington’s disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆9-tetrahydrocannabinol (∆9-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex®, is beneficial in R6/2 mice (a transgenic model of HD), as it was previously shown to have positive effects in neurotoxin-based models of HD. We recorded the progression of neurological deficits and the extent of striatal deterioration, using behavioral, in vivo imaging, and biochemical methods in R6/2 mice and their corresponding wild-type mice. The mice were daily treated, starting at 4 weeks after birth, with a Sativex-like combination of phytocannabinoids (equivalent to 3 mg/kg weight of pure CBD + ∆9-THC) or vehicle. R6/2 mice exhibited the characteristic deterioration in rotarod performance that initiated at 6 weeks and progressed up to 10 weeks, and elevated clasping behavior reflecting dystonia. Treatment with the Sativex-like combination of phytocannabinoids did not recover rotarod performance, but markedly attenuated clasping behavior. The in vivo positron emission tomography (PET) analysis of R6/2 animals at 10 weeks revealed a reduced metabolic activity in the basal ganglia, which was partially attenuated by treatment with the Sativex-like combination of phytocannabinoids. Proton nuclear magnetic resonance spectroscopy (H+-MRS) analysis of the ex vivo striatum of R6/2 mice at 12 weeks revealed changes in various prognostic markers reflecting events typically found in HD patients and animal models, such as energy failure, mitochondrial dysfunction, and excitotoxicity. Some of these changes (taurine/creatine, taurine/N-acetylaspartate, and N-acetylaspartate/choline ratios) were completely reversed by treatment with the Sativex-like combination of phytocannabinoids. A Sativex-like combination of phytocannabinoids administered to R6/2 mice at the onset of motor symptoms produced certain benefits on the progression of striatal deterioration in these mice, which supports the interest of this cannabinoid-based medicine for the treatment of disease progression in HD patients.

CRISPR/Cas9 Editing of the Mutant Huntingtin Allele In Vitro and In Vivo

Huntington disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by CAG repeat expansion (>36 repeats) within the first exon of the huntingtin gene. Although mutant huntingtin (mHTT) is ubiquitously expressed, the brain shows robust and early degeneration. Current RNA interference-based approaches for lowering mHTT expression have been efficacious in mouse models, but basal mutant protein levels are still detected. To fully mitigate expression from the mutant allele, we hypothesize that allele-specific genome editing can occur via prevalent promoter-resident SNPs in heterozygosity with the mutant allele. Here, we identified SNPs that either cause or destroy PAM motifs critical for CRISPR-selective editing of one allele versus the other in cells from HD patients and in a transgenic HD model harboring the human allele.

Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease.

Cognitive deficits associated with Huntington disease (HD) are generally dominated by executive function disorders often associated with disinhibition and impulsivity/compulsivity. Few studies have directly examined symptoms and consequences of behavioral disinhibition in HD and its relation with decision-making. To assess the different forms of impulsivity in a transgenic model of HD (tgHD rats), two tasks assessing cognitive/choice impulsivity were used: risky decision-making with a rat gambling task (RGT) and intertemporal choices with a delay discounting task (DD). To assess waiting or action impulsivity the differential reinforcement of low rate of responding task (DRL) was used. In parallel, the volume as well as cellular activity of the amygdala was analyzed. In contrast to WT rats, 15 months old tgHD rats exhibited a poor efficiency in the RGT task with difficulties to choose advantageous options, a steep DD curve as delays increased in the DD task and a high rate of premature and bursts responses in the DRL task. tgHD rats also demonstrated a concomitant and correlated presence of both action and cognitive/choice impulsivity in contrast to wild type (WT) animals. Moreover, a reduced volume associated with an increased basal cellular activity of the central nucleus of amygdala indicated a dysfunctional amygdala in tgHD rats, which could underlie inhibitory dyscontrol. In conclusion, tgHD rats are a good model for impulsivity disorder that could be used more widely to identify potential pharmacotherapies to treat these invasive symptoms in HD.

Impulsivity trait in the early symptomatic BACHD transgenic rat model of Huntington disease

Impulsivity trait was characterized in 3–5 months old BACHD rats, a transgenic model of Huntington disease, using (1) the delay discounting task to assess cognitive/choice impulsivity, and (2) the Differential Reinforcement of Low Rate of Responding task to evaluate motor/action impulsivity. Transgenic animals showed a high level of choice impulsivity and, to a lesser extent, action impulsivity. Our results provide the first evidence that the transgenic BACHD rat (TG5 line) displays impulsivity disorder as early as 3 months old, as described in early symptomatic HD patients, thus adding to the face validity of the rat model.

Expression, pharmacology and functional activity of adenosine A1 receptors in genetic models of Huntington's disease

Adenosine A1 receptor (A1R) stimulation exerts beneficial effects in response to various insults to the brain and, although it was found neuroprotective in a lesional model of Huntington's disease (HD), the features of this receptor in genetic models of HD have never been explored. In the present study we characterized the expression, affinity and functional effects of A1Rs in R6/2 mice (the most widely used transgenic model of HD) and in a cellular model of HD. Binding studies revealed that the density of A1Rs was significantly reduced in the cortex and the striatum of R6/2 mice compared to age-matched wild-type (WT), while receptor affinity was unchanged. The selective A1R agonist cyclopentyladenosine (CPA, 300nM) was significantly more effective in reducing synaptic transmission in corticostriatal slices from symptomatic R6/2 than in age-matched WT mice. Such an effect was due to a stronger inhibition of glutamate release from the pre-synaptic terminal. The different functional activities of A1Rs in HD mice were associated also to a different intracellular signaling pathway involved in the synaptic effect of CPA. In fact, while the PKA pathway was involved in both genotypes, p38 MAPK inhibitor SB203580 partially prevented synaptic effects of CPA in R6/2, but not in WT, mice; moreover, CPA differently modulated the phosphorylation status of p38 in the two genotypes. In vitro studies confirmed a different behavior of A1Rs in HD: CPA (100 nM for 5h) modulated cell viability in STHdhQ111/Q111 (mhttHD cells), without affecting the viability of STHdhQ7/Q7 (wthtt cells). This effect was prevented by the application of SB203580. Our results demonstrate that in the presence of the HD mutation A1Rs undergo profound changes in terms of expression, pharmacology and functional activity. These changes have to be taken in due account when considering A1Rs as a potential therapeutic target for this disease.

A Monoclonal Antibody TrkB Receptor Agonist as a Potential Therapeutic for Huntington’s Disease

Huntington’s disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.

Tracking Brain Palmitoylation Change: Predominance of Glial Change in a Mouse Model of Huntington’s Disease

Protein palmitoylation, a reversible lipid modification of proteins, is widely used in the nervous system, with dysregulated palmitoylation being implicated in a variety of neurological disorders. Described below is ABE/SILAM, a proteomic strategy that couples acyl-biotinyl exchange (ABE) purification of palmitoyl-proteins to whole animal stable isotope labeling (SILAM) to provide an accurate tracking of palmitoylation change within rodent disease models. As a first application, we have used ABE/SILAM to look at Huntington's disease (HD), profiling palmitoylation change in two HD-relevant mouse mutants: the transgenic HD model mouse YAC128 and the hypomorphic Hip14-gt mouse, which has sharply reduced expression for HIP14 (Zdhhc17), a palmitoyl-transferase implicated in the HD disease process. Rather than mapping to the degenerating neurons themselves, the biggest disease changes instead map to astrocytes and oligodendrocytes (i.e., the supporting glial cells).

A neuroprotective phase precedes striatal degeneration upon nucleolar stress

The nucleolus is implicated in sensing and responding to cellular stress by stabilizing p53. The pro-apoptotic effect of p53 is associated with several neurodegenerative disorders, including Huntington's disease (HD), which is characterized by the progressive loss of medium spiny neurons (MSNs) in the striatum. Here we show that disruption of nucleolar integrity and function causes nucleolar stress and is an early event in MSNs of R6/2 mice, a transgenic model of HD. Targeted perturbation of nucleolar function in MSNs by conditional knockout of the RNA polymerase I-specific transcription initiation factor IA (TIF-IA) leads to late progressive striatal degeneration, HD-like motor abnormalities and molecular signatures. Significantly, p53 prolongs neuronal survival in TIF-IA-deficient MSNs by transient upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor that inhibits mammalian target of rapamycin signaling and induces autophagy. The results emphasize the initial role of nucleolar stress in neurodegeneration and uncover a p53/PTEN-dependent neuroprotective response.

Finding the striatum in sheep: use of a multi-modal guided approach for convection enhanced delivery.

Our goal is delivery of a long-term treatment for Huntington's disease. We administer intracerebrally in sheep adeno-associated virus (AAV) to establish optimal safety, spread and neuronal uptake of AAV based therapeutics. Sheep have large gyrencephalic brains and offer the opportunity to study a transgenic Huntington's disease model. However, lack of a relevant brain stereotactic atlas and the difficulty of skull fixation make conventional stereotaxy unreliable. We describe a multi-modal image-guidance technique to achieve accurate placement of therapeutics into the sheep striatum.

A transgenic minipig model of Huntington's Disease.

Some promising treatments for Huntington's disease (HD) may require pre-clinical testing in large animals. Minipig is a suitable species because of its large gyrencephalic brain and long lifespan. To generate HD transgenic (TgHD) minipigs encoding huntingtin (HTT)1-548 under the control of human HTT promoter. Transgenesis was achieved by lentiviral infection of porcine embryos. PCR assessment of gene transfer, observations of behavior, and postmortem biochemical and immunohistochemical studies were conducted. One copy of the human HTT transgene encoding 124 glutamines integrated into chromosome 1 q24-q25 and successful germ line transmission occurred through successive generations (F0, F1, F2 and F3 generations). No developmental or gross motor deficits were noted up to 40 months of age. Mutant HTT mRNA and protein fragment were detected in brain and peripheral tissues. No aggregate formation in brain up to 16 months was seen by AGERA and filter retardation or by immunostaining. DARPP32 labeling in WT and TgHD minipig neostriatum was patchy. Analysis of 16 month old sibling pairs showed reduced intensity of DARPP32 immunoreactivity in neostriatal TgHD neurons compared to those of WT. Compared to WT, TgHD boars by one year had reduced fertility and fewer spermatozoa per ejaculate. In vitro analysis revealed a significant decline in the number of WT minipig oocytes penetrated by TgHD spermatozoa. The findings demonstrate successful establishment of a transgenic model of HD in minipig that should be valuable for testing long term safety of HD therapeutics. The emergence of HD-like phenotypes in the TgHD minipigs will require more study.

Dysfunctional Behavioral Modulation of Corticostriatal Communication in the R6/2 Mouse Model of Huntington’s Disease

BackgroundIn Huntington’s disease (HD), motor symptoms develop prior to the widespread loss of neurons in striatum and cerebral cortex. The aim of this study was to examine dysfunctional patterns of corticostriatal communication during spontaneously occurring behaviors in a transgenic mouse model of HD.Methodology/Principal FindingsLocal field potentials (LFPs) were recorded from two closely interconnected areas, motor cortex and dorsal striatum, in wild-type controls (WT, n = 14) and a widely used transgenic HD model (R6/2 mice, n = 12). All mice were between the ages of 7–9 weeks, a critical period of motor symptom development in R6/2s. Recordings were obtained while the mice were behaving freely in an open field. Specific LFP activity was extracted using timestamps for three increasingly demanding motor behaviors: 1) resting; 2) grooming; and 3) active exploration. Power spectral densities (PSD) were obtained for the cortical and striatal LFPs as well as coherence levels and relative phase across the frequency spectrum. In both brain regions, only R6/2s showed high frequency LFP oscillations during rest and grooming. As behavior increased from resting to exploring, corticostriatal synchrony at high frequencies declined in R6/2s, completely opposite to the WT pattern. R6/2s also exhibited nearly in-phase corticostriatal activity (cortex phase leads of ∼5°), while the WTs consistently showed cortical phase lags of ∼20° across all assessed behaviors, indicating a lead role for striatum.Conclusions/SignificanceOur results add to growing evidence for altered communication between cortex and striatum in HD and suggest more generally that increasingly demanding motor behaviors differentially modulate corticostriatal communication. Our data also suggest conduction delays in R6/2 corticostriatal transmission, leading to compensatory speeding of LFP activity, as evidenced by the presence of high frequency LFP oscillations.

Comparative analyses of Purkinje cell gene expression profiles reveal shared molecular abnormalities in models of different polyglutamine diseases

Polyglutamine (PolyQ) diseases have common features that include progressive selective neurodegeneration and the formation of protein aggregates. There is growing evidence to suggest that critical nuclear events lead to transcriptional alterations in PolyQ diseases such as spinocerebellar ataxia type 7 (SCA7) and Huntington's disease (HD), conditions which share a cerebellar degenerative phenotype. Taking advantage of laser capture microdissection technique, we compared the Purkinje cell (PC) gene expression profiles of two transgenic polyQ mouse models (HD: R6/2; SCA7: P7E) by microarray analysis that was validated by real time quantitative PCR. A large number of transcriptional alterations were detected in the R6/2 transgenic model of HD. Similar decreases in the same mRNAs, such as phospholipase C, β 3, purkinje cell protein 2 (Pcp2) and aldolase C, were found in both models. A decrease in aldolase C and phospholipase C, β 3, may lead to an increase in the vulnerability of PCs to excitotoxic events. Furthermore, downregulation of mRNAs mediated by the Pcp2-promoter is common in both models. Thus, our data reveal shared molecular abnormalities in different polyQ disorders.