Age- and sex-related changes in cortical and striatal nitric oxide synthase in the Q175 mouse model of Huntington's disease

Padovan-Neto, Fernando E.; Jurkowski, Lauren; Murray, Conor H.; Stutzmann, Grace E.; Kwan, Mei; Ghavami, Afshin; Beaumont, Vahri; Park, Larry C.; West, Anthony R.

doi:10.1016/j.niox.2018.12.002

Cited by 24 publications

(18 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the up-regulation of MOR1 in the Q175KI striatum is an early change, suggesting that it might not be, at least initially, solely compensatory. Also, this change is a histological confirmation of instances of upregulation, as opposed to down-regulation, of neuronal proteins seen in proteomic and PET studies in HD and in the Q175KI HD model (Ferrante et al, 1985(Ferrante et al, , 1987Reiner et al, 1988Reiner et al, , 2013Goto et al, 1989;Albin et al, 1990Albin et al, , 1992Morton et al, 1993;Hedreen and Folstein, 1995;Augood et al, 1996;Cicchetti et al, 2000;Tippett et al, 2007;Smith et al, 2014;Langfelder et al, 2016;Wilson et al, 2017;Padovan-Neto et al, 2019). Given that MOR1 mRNA in Q175KI mice was not up-regulated in the striatum at the age of 2, 6, and 10 months (Langfelder et al, 2016), as judged by immunohistochemistry, MOR1 up-regulation in our study may be thought to occur in posttranscriptional or posttranslational manner, for example, due to dysregulation in alternative splicing, the consequence of protein-protein interaction, or compensation to the changes in the expression levels in other proteins.…”

Section: Discussionsupporting

confidence: 56%

Spatiotemporal Up-Regulation of Mu Opioid Receptor 1 in Striatum of Mouse Model of Huntington’s Disease Differentially Affecting Caudal and Striosomal Regions

et al. 2020

View full text Add to dashboard Cite

The striatum of humans and other mammals is divided into macroscopic compartments made up of a labyrinthine striosome compartment embedded in a much larger surrounding matrix compartment. Anatomical and snRNA-Seq studies of the Huntington’s disease (HD) postmortem striatum suggest a preferential decline of some striosomal markers, and mRNAs studies of HD model mice concur. Here, by immunohistochemical methods, we examined the distribution of the canonical striosomal marker, mu-opioid receptor 1 (MOR1), in the striatum of the Q175 knock-in mouse model of HD in a postnatal time series extending from 3 to 19 months. We demonstrate that, contrary to the loss of many markers for striosomes, there is a pronounced up-regulation of MOR1 in these Q175 knock-in mice. We show that in heterozygous Q175 knock-in model mice [~192 cytosine-adenine-guanine (CAG) repeats], this MOR1 up-regulation progressed with advancing age and disease progression, and was particularly remarkable at caudal levels of the striatum. Given the known importance of MOR1 in basal ganglia signaling, our findings, though in mice, should offer clues to the pathogenesis of psychiatric features, especially depression, reinforcement sensitivity, and involuntary movements in HD.

show abstract

Section: Discussionsupporting

confidence: 56%

Spatiotemporal Up-Regulation of Mu Opioid Receptor 1 in Striatum of Mouse Model of Huntington’s Disease Differentially Affecting Caudal and Striosomal Regions

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In general, our findings show that neurochemical pathologies and behavioral abnormalities develop between 2 and 6 months of age in male heterozygous Q175 mice, and the overall level of neuropathology achieved by 18 months of age is less severe than that seen in humans at a premanifest stage of HD. Since prior studies have found no major difference between males and females in the Q175 phenotype (Goodliffe et al, 2018;Menalled et al, 2012;Padovan-Neto et al, 2019;Rothe et al, 2015), it is likely this is true of female Q175 heterozygotes as well.…”

Section: Discussionmentioning

confidence: 91%

Progression of basal ganglia pathology in heterozygous Q175 knock‐in Huntington's disease mice

Deng

Wang

Joni

et al. 2020

J of Comparative Neurology

View full text Add to dashboard Cite

We used behavioral testing and morphological methods to detail the progression of basal ganglia neuron type-specific pathology and the deficits stemming from them in male heterozygous Q175 mice, compared to age-matched WT males. A rotarod deficit was not present in Q175 mice until 18 months, but increased open field turn rate (reflecting hyperkinesia) and open field anxiety were evident at 6 months. No loss of striatal neurons was seen out to 18 months, but ENK+ and DARPP32+ striatal perikarya were fewer by 6 months, due to diminished expression, with further decline by 18 months. No reduction in SP+ striatal perikarya or striatal interneurons was seen in Q175 mice at 18 months, but cholinergic interneurons showed dendrite attenuation by 6 months. Despite reduced ENK expression in indirect pathway striatal perikarya, ENK-immunostained terminals in globus pallidus externus (GPe) were more abundant at 6 months and remained so out to 18 months. Similarly, SP-immunostained terminals from striatal direct pathway neurons were more abundant in globus pallidus internus and substantia nigra at 6 months and remained so at 18 months. FoxP2+ arkypallidal GPe neurons and subthalamic nucleus neurons were lost by 18 months but not prototypical PARV+ GPe neurons or dopaminergic nigral neurons. Our results show that striatal projection neuron abnormalities and behavioral abnormalities reflecting them develop between 2 and 6 months of age in Q175 male heterozygotes, indicating early effects of the HD mutation. The striatal pathologies resemble those in human HD, but are less severe at 18 months than even in premanifest HD.

show abstract

“…Also animal studies, confirming gender differences, bring contrary results of gender burden, displaying their ample limitations in explanation of pathologic processes behind observed differences ( 50 – 53 ). The findings in animal models suggest their imperfection rather ( 55 ).…”

Section: Discussionmentioning

confidence: 97%

“…In 2016 in BACHD mouse model of Huntington's disease, it was found that circadian activity levels, rhythm precision, and behavioral fragmentation are more severe in males (52). Finally, in 2019 more severe deficits in neuroprotective nitric oxide synthase activity in the HD cortex and striatum were observed mostly in Q175 males of HD mouse model (53). In contrast to human studies, animal research results indicate a more severe picture in males.…”

Section: Sex Plays a Rolementioning

confidence: 98%

Gender Differences in Non-sex Linked Disorders: Insights From Huntington's Disease

Zielonka

Stawińska-Witoszyńska

2020

Front. Neurol.

View full text Add to dashboard Cite

Age- and sex-related changes in cortical and striatal nitric oxide synthase in the Q175 mouse model of Huntington's disease

Cited by 24 publications

References 59 publications

Spatiotemporal Up-Regulation of Mu Opioid Receptor 1 in Striatum of Mouse Model of Huntington’s Disease Differentially Affecting Caudal and Striosomal Regions

Spatiotemporal Up-Regulation of Mu Opioid Receptor 1 in Striatum of Mouse Model of Huntington’s Disease Differentially Affecting Caudal and Striosomal Regions

Progression of basal ganglia pathology in heterozygous Q175 knock‐in Huntington's disease mice

Gender Differences in Non-sex Linked Disorders: Insights From Huntington's Disease

Contact Info

Product

Resources

About