A deconvolution method to improve automated 3D-analysis of dendritic spines: application to a mouse model of Huntington’s disease

Heck, Nicolas; Bétuing, Sandrine; Vanhoutte, Peter; Caboche, Jocelyne

doi:10.1007/s00429-011-0340-y

Cited by 48 publications

(32 citation statements)

References 71 publications

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“…The brains were removed and post-fixed for 1 h in the same fixative, and sections (150 μm) were cut with a vibratome. 21 Image stacks of MSN dendrites were acquired in the NAc shell using a 488 or 561-nm laser line for excitation of a Confocal Laser Scanning Microscope (SP5, Leica, Wetzlar, Germany). Image stacks were deconvoluted with Huygens 3.5 software (Scientific Volume Imaging).…”

Section: Diolistic Labeling and Dendritic Spine Analysismentioning

confidence: 99%

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens

et al. 2015

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Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

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Section: Diolistic Labeling and Dendritic Spine Analysismentioning

confidence: 99%

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens

et al. 2015

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“…growth and modulation of synaptic strength (41)(42)(43). Given that dysregulated neuronal morphology and altered synaptic strength occur in HD (44)(45)(46), the proteasome-mediated regulation of synaptic remodeling might be impaired in HD and is likely to play a critical role in HD pathogenesis. Collectively, these findings suggest that enhanced phosphorylation of Rpt6 at Ser 120 by PKA and CaMKII␣ provides a potential route to identify new therapeutic agents for treating HD.…”

Section: Figmentioning

confidence: 99%

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Lin

Chang

Chen

et al. 2013

Molecular and Cellular Biology

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Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG repeat in the Huntingtin (HTT) gene. Abnormal regulation of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway occurs during HD progression. Here we found that lower PKA activity was associated with proteasome impairment in the striatum for two HD mouse models (R6/2 and N171-82Q) and in mutant HTT (mHTT)-expressing striatal cells. Because PKA regulatory subunits (PKA-Rs) are proteasome substrates, the mHTT-evoked proteasome impairment caused accumulation of PKA-Rs and subsequently inhibited PKA activity. Conversely, activation of PKA enhanced the phosphorylation of Rpt6 (a component of the proteasome), rescued the impaired proteasome activity, and reduced mHTT aggregates. The dominant-negative Rpt6 mutant (Rpt6 S120A ) blocked the ability of a cAMP-elevating reagent to enhance proteasome activity, whereas the phosphomimetic Rpt6 mutant (Rpt6 S120D ) increased proteasome activity, reduced HTT aggregates, and ameliorated motor impairment. Collectively, our data demonstrated that positive feedback regulation between PKA and the proteasome is critical for HD pathogenesis. Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG repeat in the Huntingtin (HTT) gene. The normal HTT gene has 35 or fewer CAG repeats in its N-terminal region, whereas expansion of the repeat beyond 35 units confers toxicity to the Huntingtin protein (HTT) and evokes HD pathogenesis (1). The major clinical presentations of HD include chorea, cognitive decline, psychiatric symptoms, and a systemic metabolic defect (2). Selective neuronal loss occurs in multiple brain regions, particularly in the striatum and cortex. Since a great number of cellular machineries (including transcription, vesicle transport, molecular chaperones, and the ubiquitin-proteasome system [UPS]) are compromised by the expression of mutant HTT (mHTT) (3), effective removal of mHTT has become one of the most challenging aspects of drug development for HD.The UPS, which degrades misfolded and/or damaged proteins in eukaryotes, is the major regulatory proteolytic pathway. It regulates many essential cellular processes, including transcription, translation, DNA repair, chromatin remodeling, cell survival, signal transduction, protein trafficking, and synaptic plasticity (4). A recent study demonstrated that AAA-ATPase subunits are critical for cell-type-specific regulation of UPS activity (5). Interestingly, UPS activity is under metabolic control. Posttranslational modifications, such as O-GlcNacylation and phosphorylation of 19S subunits, affect the proteolytic activity of the UPS (6). In addition, impaired functioning of the UPS is believed to contribute to the pathogenic processes of many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease (PD), and HD. Recent studies revealed that the UPS might be impaired in HD mouse models and patients (7,8). Intriguingly, although the degradation of polyubiquitin-tagg...

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“…1); thus, ROR␣ is present during the embryonic (E14, Hamilton et al, 1996) and early postnatal period and is then no longer synthesized starting at an age when CF synapse elimination is well underway or nearly complete (Kano and Hashimoto, 2009). Our morphological studies revealed dendritic changes and particularly a reversal of the CF somatodendritic translocation, suggesting functional changes in the CF/PC synapses.…”

Section: Rora Deletion In Pcs After the First Postnatal Week Triggersmentioning

confidence: 99%

Mature Purkinje Cells Require the Retinoic Acid-Related Orphan Receptor-α (RORα) to Maintain Climbing Fiber Mono-Innervation and Other Adult Characteristics

et al. 2013

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Neuronal maturation during development is a multistep process regulated by transcription factors. The transcription factor ROR␣ (retinoic acid-related orphan receptor ␣) is necessary for early Purkinje cell (PC) maturation but is also expressed throughout adulthood. To identify the role of ROR␣ in mature PCs, we used Cre-lox mouse genetic tools in vivo that delete it specifically from PCs between postnatal days 10 -21. Up to 14 d of age, differences between mutant and control PCs were not detectable: both were mono-innervated by climbing fibers (CFs) extending along their well-developed dendrites with spiny branchlets. By week 4, mutant mice were ataxic, some PCs had died, and remaining PC soma and dendrites were atrophic, with almost complete disappearance of spiny branchlets. The innervation pattern of surviving ROR␣-deleted PCs was abnormal with several immature characteristics. Notably, multiple functional CF innervation was reestablished on these mature PCs, simultaneously with the relocation of CF contacts to the PC soma and their stem dendrite. This morphological modification of CF contacts could be induced even later, using lentivirus-mediated depletion of rora from adult PCs. These data show that the late postnatal expression of ROR␣ cell-autonomously regulates the maintenance of PC dendritic complexity, and the CF innervation status of the PC (dendritic vs somatic contacts, and mono-innervation vs multi-innervation). Thus, the differentiation state of adult neurons is under the control of transcription factors; and in their absence, adult neurons lose their mature characteristics and acquire some characteristics of an earlier developmental stage.

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A deconvolution method to improve automated 3D-analysis of dendritic spines: application to a mouse model of Huntington’s disease

Cited by 48 publications

References 71 publications

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Mature Purkinje Cells Require the Retinoic Acid-Related Orphan Receptor-α (RORα) to Maintain Climbing Fiber Mono-Innervation and Other Adult Characteristics

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