Alterations in synaptic function and plasticity in Huntington disease

Smith-Dijak, Amy; Sepers, Marja D.; Raymond, Lynn A.

doi:10.1111/jnc.14723

Cited by 103 publications

(70 citation statements)

References 209 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another important signaling pathway that may be involved in the reduction of the photic regulation of the circadian system is brain‐derived neurotrophic factor (BDNF). Deficits in BDNF expression, trafficking, and signaling have been found in tissue from HD patients and HD mouse models (e.g., Smith‐Dijak, Sepers, & Raymond, ; Zuccato & Cattaneo, ). BDNF also appears to be an important regulator of synaptic input into the SCN.…”

Section: Resultsmentioning

confidence: 99%

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

Smarr

Cutler

Loh

et al. 2019

J of Neuroscience Research

View full text Add to dashboard Cite

Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, have been the topic of a number of recent studies. The (z)Q175 mouse is a knock‐in model in which the human exon 1 sequence of the huntingtin gene is inserted into the mouse DNA with approximately 190 CAG repeats. Among the numerous models available, the heterozygous Q175 offers strong construct validity with a single copy of the mutation, genetic precision of the insertion and control of mutation copy number. In this review, we will summarize the evidence that this model exhibits disrupted diurnal and circadian rhythms in locomotor activity. We found overwhelming evidence for autonomic dysfunction including blunted daily rhythms in heart rate and core body temperature (CBT), reduced heart rate variability, and almost a complete failure of the sympathetic arm of the autonomic nervous system to function during the baroreceptor reflex. Mechanistically, the Q175 mouse model exhibits deficits in the neural output of the central circadian clock, the suprachiasmatic nucleus along with an enhancement of at least one type of potassium current in these neurons. Finally, we report a novel network analysis examining the phase coherence between activity, CBT, and cardiovascular measures. Such analyses found that even young Q175 mutants (heterozygous or homozygous) show coherence degradation, and suggests that loss of phase coherence is a variable that should be considered as a possible biomarker for HD.

show abstract

Section: Resultsmentioning

confidence: 99%

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

Smarr

Cutler

Loh

et al. 2019

J of Neuroscience Research

View full text Add to dashboard Cite

show abstract

“…In HD models, despite the survival of CINs in the striatum, a dysregulation of acetylcholine release has been reported (Reiner and Deng, 2018). By this mechanism, increased levels of DA would exacerbate the imbalance toward activation of the direct pathway, and promote the development of HD symptoms (Smith-Dijak et al, 2019).…”

Section: Dopaminergic Modulationmentioning

confidence: 99%

Cortical and Striatal Circuits in Huntington’s Disease

Blumenstock

Dudanova

2020

Front. Neurosci.

View full text Add to dashboard Cite

Huntington's disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

show abstract

“…as such, it is speculated that PrcP and MaPK10 may regulate Bn by mediating the release of special neurotransmitters, which in turn may regulate bone remodeling (33,34). indeed, synaptic function is known to be regulated by endocannabinoids, which are lipid signaling molecules that regulate signaling within the central nervous system (35). This may explain the downregulation of PrcP and MaPK10 in the Bn patients of the present study.…”

Section: Discussionmentioning

confidence: 53%

Identification of key microRNAs and target genes for the diagnosis of bone nonunion

et al. 2020

View full text Add to dashboard Cite

a number of recent studies have highlighted the causes of bone nonunion (Bn), however, the rate of Bn incidence continues to rise and available therapeutic options to treat this condition remain limited. Thus, to prevent disease progression and improve patient prognosis, it is vital that BN, or the risk thereof, be accurately identified in a timely manner. in the present study, bioinformatics analyses were used to screen for the differentially expressed genes (deGs) and differentially expressed mirnas (deMs) between patients with Bn and those with bone union, using data from the Gene expression omnibus database. Furthermore, clinical samples were collected and analyzed by reverse transcription-quantitative Pcr and western blotting. In vitro and in vivo experiments were carried out to confirm the relationship between Bn and the deGs of interest, in addition to being used to explore the underlying molecular mechanism of Bn. Functional enrichment analysis of the downregulated deGs revealed them to be enriched for genes associated with 'ecM-receptor interactions', 'focal adhesion', 'and the calcium signaling pathway'. When comparing deM target genes with these DEGs, nine DEGs were identified as putative deM targets, where hsa-microrna (mir)-1225-5p-ccnl2, hsa-mir-339-5p-PrcP, and hsa-mir-193a-3p-mitogen-activated protein kinase 10 (MaPK10) were the only three pairs which were associated with decreased gene expression levels. Furthermore, hsa-mir-193a-3p was demonstrated to induce Bn by targeting MaPK10. collectively, the results of the present study suggest that hsa-mir-193a-3p may be a viable biomarker of Bn.

show abstract

Alterations in synaptic function and plasticity in Huntington disease

Cited by 103 publications

References 209 publications

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

Cortical and Striatal Circuits in Huntington’s Disease

Identification of key microRNAs and target genes for the diagnosis of bone nonunion

Contact Info

Product

Resources

About