Decreased dendritic spine density as a consequence of tetanus toxin light chain expression in single neurons in vivo

Heimer-McGinn, Victoria; Murphy, Anita C.H.; Kim, Jun Chul; Dymecki, Susan M.; Young, Paul

doi:10.1016/j.neulet.2013.09.007

Cited by 9 publications

(7 citation statements)

References 24 publications

(49 reference statements)

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“…The impairments in the exocytosis and neurotransmitter release at the pre-synapse due to the inhibition of the PS1-Syt1 interaction lead to the concomitant reduction in the number of dendritic spines, and mushroom spines in particular. This finding is consistent with the previous observations of decreased spine density in vivo following the expression of potent exocytosis inhibitors [ 69 ] and in AD models, as reviewed in [ 70 , 71 ]. Together, with our findings of the detrimental effect of PS1-LNT blocking peptide treatment on PS1 conformation, Aβ42/40 ratio and intracellular Aβ accumulation, this further supports the beneficial role of the PS1-Syt1 interaction for synaptic wellbeing.…”

Section: Discussionsupporting

confidence: 93%

Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid β production

Zoltowska

Maesako

Lushnikova

et al. 2017

Mol Neurodegeneration

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BackgroundAlzheimer’s disease (AD)-linked protein, presenilin 1 (PS1), is present at the synapse, and the knock-out of presenilin in mice leads to synaptic dysfunction. On the other hand, synaptic activity was shown to influence PS1-dependent generation of distinct amyloid β (Aβ) species. However, the precise nature of these regulations remains unclear. The current study reveals novel role of PS1 at the synapse, and deciphers how PS1 and synaptic vesicle-associated protein, synaptotagmin 1 (Syt1) modulate each other functions in neurons via direct activity-triggered interaction. Additionally, the therapeutic potential of fostering PS1-Syt1 binding is investigated as a synapse-specific strategy for AD prevention.MethodsPS1-based cell-permeable peptide targeting PS1-Syt1 binding site was designed to inhibit PS1-Syt1 interaction in neurons. PS1 conformation, synaptic vesicle exocytosis and trafficking were assayed by fluorescence lifetime imaging microscopy (FLIM), glutamate release/synaptopHluorin assay, and fluorescence recovery after photobleaching, respectively. Syt1 level and interaction with PS1 in control and sporadic AD brains were determined by immunohistochemistry and FLIM. AAV-mediated delivery of Syt1 into mouse hippocampi was used to investigate the therapeutic potential of strengthening PS1-Syt1 binding in vivo. Statistical significance was determined using two-tailed unpaired Student’s t-test, Mann-Whitney’s U-test or two-way ANOVA followed by a Bonferroni’s post-test.ResultsWe demonstrate that targeted inhibition of the PS1-Syt1 binding in neurons, without changing the proteins’ expression level, triggers “pathogenic” conformational shift of PS1, and consequent increase in the Aβ42/40 ratio. Moreover, our data indicate that PS1, by binding directly to Syt1, regulates synaptic vesicle trafficking and facilitates exocytosis and neurotransmitter release. Analysis of human brain tissue revealed that not only Syt1 levels but also interactions between remaining Syt1 and PS1 are diminished in sporadic AD. On the other hand, overexpression of Syt1 in mouse hippocampi was found to potentiate PS1-Syt1 binding and promote “protective” PS1 conformation.ConclusionsThe study reports novel functions of PS1 and Syt1 at the synapse, and demonstrates the importance of PS1-Syt1 binding for exocytosis and safeguarding PS1 conformation. It suggests that reduction in the Syt1 level and PS1-Syt1 interactions in AD brain may present molecular underpinning of the pathogenic PS1 conformation, increased Aβ42/40 ratio, and impaired exocytosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0159-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid β production

Zoltowska

Maesako

Lushnikova

et al. 2017

Mol Neurodegeneration

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“…To determine the necessity of the Npy1R MeA population for satiety, territorial aggression, and high-risk exploration, we used a viral approach to chronically inhibit Npy1r Cre -expressing cells in the MeA. Mice were transduced with a conditional virus containing the light-chain of the tetanus toxin (AAV1-DIOGFP:TetTox) which can silence neurons by preventing synaptic transmission 35 , 36 ( Fig. 3h ).…”

Section: Resultsmentioning

confidence: 99%

Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state

et al. 2016

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In the face of starvation animals will engage in high-risk behaviors that would normally be considered maladaptive. Starving rodents for example will forage in areas that are more susceptible to predators and will also modulate aggressive behavior within a territory of limited or depleted nutrients. The neural basis of these adaptive behaviors likely involves circuits that link innate feeding, aggression, and fear. Hypothalamic AgRP neurons are critically important for driving feeding and project axons to brain regions implicated in aggression and fear. Using circuit-mapping techniques, we define a disynaptic network originating from a subset of AgRP neurons that project to the medial nucleus of the amygdala and then to the principle bed nucleus of the stria terminalis, which plays a role in suppressing territorial aggression and reducing contextual fear. We propose that AgRP neurons serve as a master switch capable of coordinating behavioral decisions relative to internal state and environmental cues.

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“…For analysis of the active lever presses and infusions during self-administration and extinction training, we used repeated measures two-way ANOVA. Nested ANOVA analysis was performed on all groups for assessment of morphometric properties, synaptic colocalization and PSD-95 expression ( Heimer-McGinn et al, 2013 ; Risher et al, 2014 ). The comparison of properties of saline-treated astrocytes across brain areas ( Table 1 ) was performed using Tukey-Kramer post hoc analysis, and comparison of behavior between cocaine and saline-administering rats on specific days ( Figure 1 ) was performed using Bonferroni post hoc analysis.…”

Section: Methodsmentioning

confidence: 99%

Region-Specific Reductions in Morphometric Properties and Synaptic Colocalization of Astrocytes Following Cocaine Self-Administration and Extinction

Testen

Sepulveda-Orengo

Gaines

et al. 2018

Front. Cell. Neurosci.

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While much is known about the effects of cocaine use on the cellular structure and function of neurons and synapses within the brain’s reward circuitry, relatively little is known about the effects of cocaine on astrocytes. Given the significant role that astrocytes play in modulating neuronal and synaptic function, this lack of knowledge regarding the role of astroglial adaptations in the neuropathology of drug abuse represents an important investigative need. We recently showed that astrocytes within the nucleus accumbens (NAc) core exhibit decreased volume, surface area, and synaptic colocalization following cocaine self-administration and extinction, compared to NAc astrocytes from saline-administering animals (Scofield et al., 2016b). However, it is unknown whether these cocaine-dependent changes in astrocytes are ubiquitous throughout the brain’s reward circuitry, or represent specific adaptations within the NAc. It is also not known whether the extinction period is necessary for the retracted phenotype, or whether self-administration alone is sufficient to drive these changes. In the current study, we have extended our assessment of the effects of cocaine self-administration on morphometric properties and synaptic colocalization of astrocyte peripheral processes in the prelimbic region of the medial prefrontal cortex (PL) and basolateral nucleus of the amygdala (BLA), both known to also contribute significantly to motivated behaviors. In addition, in order to pinpoint the temporal dimension of previously observed effects, we also examined astrocytes within the NAc following the last self-administration session. While a reduction of astrocyte size and synaptic colocalization was observed in the NAc core of cocaine-extinguished rats as previously shown, no differences in PL or BLA astrocytes were observed between saline- and cocaine-extinguished rats. Moreover, decreased synaptic colocalization of peripheral processes in the NAc was observed with a post-synaptic marker, instead of a presynaptic marker as used previously. In contrast, no significant changes were found in NAc astrocytes after self-administration alone. These results provide insights into the influence of cocaine use on astrocytes within the brain reward circuitry, and inform both regional heterogeneity as well as temporal dynamics of astrocyte responsiveness to cocaine self-administration.

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Decreased dendritic spine density as a consequence of tetanus toxin light chain expression in single neurons in vivo

Cited by 9 publications

References 24 publications

Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid β production

Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid β production

Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state

Region-Specific Reductions in Morphometric Properties and Synaptic Colocalization of Astrocytes Following Cocaine Self-Administration and Extinction

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