Microglial activation in the dorsal striatum participates in anxiety-like behavior in Cyld knockout mice

Han, Yuanyuan; Jin, Kai; Pan, Qi-Sheng; Li, Bo; Wu, Zhuo-Qing; Gan, Lin; Yang, Li; Long, Cheng

doi:10.1016/j.bbi.2020.07.011

Cited by 28 publications

(21 citation statements)

References 79 publications

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“…A previous report showed that Cyld −/− mice exhibited normal motor function and did not show depressionlike behavior (Han et al, 2020). However, anxiety-like behavior was found in Cyld −/− mice (Han et al, 2020). In the current study, Cyld −/− and Cyld +/+ mice showed a similar freezing response during the habituation and pre-tone period, thus excluding the influence of anxiety.…”

Section: Discussionsupporting

confidence: 51%

“…We also consider other factors that may affect the fear behavior. A previous report showed that Cyld −/− mice exhibited normal motor function and did not show depressionlike behavior (Han et al, 2020). However, anxiety-like behavior was found in Cyld −/− mice (Han et al, 2020).…”

Section: Discussionmentioning

confidence: 93%

“…As previously described (Han et al, 2020), mice were anesthetized and perfused transcardially with 4% paraformaldehyde (PFA) in phosphate buffer saline (PBS), and tissues were fixed in 4% PFA at 4 • C for 12 h. After dehydration by 30% sucrose, brain tissue was cut into 30-µm-thick sections using a freezing microtome (Leica CM30505, Germany). The posterior portion of the BLAcontaining sections was permeabilized with 0.3% Triton X-100 and 5% donkey serum in PBS for 2 h and then incubated with rabbit polyclonal anti-c-Fos antibody (1:1,000, Abcam, Cambridge, United Kingdom, ab190289) or rabbit polyclonal anti-PV antibody (1:1,000, Abcam, ab11427) at 4 • C overnight.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Deficiency of the CYLD Impairs Fear Memory of Mice and Disrupts Neuronal Activity and Synaptic Transmission in the Basolateral Amygdala

Yang

et al. 2021

Front. Cell. Neurosci.

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Fear learning and memory are crucial for animal survival. Abnormal fear memory is a hallmark of many neuropsychiatric disorders. Appropriate neuronal activation and excitability in the basolateral amygdala (BLA) are necessary for the formation of fear memory. The gene cylindromatosis (Cyld), which encodes a lysine-63 deubiquitinase, is expressed in several brain regions including the amygdala. The functions of the cylindromatosis protein (CYLD) in the regulation of the neuronal activity, neural circuits and fear memory, remain largely unknown, however. Here, we report that Cyld knockout impairs amygdala-dependent tone-cued fear memory. The number of c-Fos+ neurons responding to the tone-cued fear test was reduced in the BLA of Cyld–/– mice, suggesting that the absence of CYLD causes aberrant neuronal activation. We found that this aberrant neuronal activation in the BLA of Cyld–/– mice may relate to the decreased excitability of principal neurons. Another possibility of aberrant neuronal activation could be the impaired excitatory synaptic transmission in the BLA of Cyld–/– mice. Specifically, both the frequency of spontaneous excitatory postsynaptic currents and the amplitude of miniature excitatory postsynaptic currents in BLA principal neurons were decreased. In addition, Cyld mutation caused an increase in both the frequency of miniature inhibitory postsynaptic currents in principal neurons and the number of parvalbumin+ interneurons, consistent with excessive local circuit inhibition in the BLA of Cyld–/– mice. Taken together, these results suggest that CYLD deficiency disrupts the neuronal activity and synaptic transmission in the BLA of mice which may contribute to the impaired fear memory observed in Cyld–/– mice.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 93%

Section: Immunohistochemistrymentioning

confidence: 99%

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Deficiency of the CYLD Impairs Fear Memory of Mice and Disrupts Neuronal Activity and Synaptic Transmission in the Basolateral Amygdala

Yang

et al. 2021

Front. Cell. Neurosci.

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“…Our study establishes that CYLD is required to maintain an array of behaviors. The anxiety-like behavior observed in CYLD KO mice is consistent with a recent study [71]. In comparison, the role of CYLD in depression and social behavior has not been previously demonstrated.…”

Section: Discussionsupporting

confidence: 92%

Cylindromatosis Drives Synapse Pruning and Weakening by Promoting Macroautophagy through Akt-mTOR Signaling

Yao

Zajicek

Dai

et al. 2021

Preprint

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The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux and, conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.

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“…Conditional knockout of parkin in adult mice leads to degeneration of dopamine neurons that is dependent on PARIS (8,9). CYLD is expressed in multiple regions of the mouse brain (16)(17)(18), including the substantia nigra (SN) dopamine neurons, where it predominantly localizes to the cytosol (Fig. 6A).…”

Section: Conditional Kd Of Cyld In Adult Mice Prevents Da Neurodegene...mentioning

confidence: 99%

Deubiquitinase CYLD acts as a negative regulator of dopamine neuron survival in Parkinson’s disease

et al. 2022

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Mutations in PINK1 and parkin highlight the mitochondrial axis of Parkinson’s disease (PD) pathogenesis. PINK1/parkin regulation of the transcriptional repressor PARIS bears direct relevance to dopamine neuron survival through augmentation of PGC-1α–dependent mitochondrial biogenesis. Notably, knockout of PARIS attenuates dopaminergic neurodegeneration in mouse models, indicating that interventions that prevent dopaminergic accumulation of PARIS could have therapeutic potential in PD. To this end, we have identified the deubiquitinase cylindromatosis (CYLD) to be a regulator of PARIS protein stability and proteasomal degradation via the PINK1/parkin pathway. Knockdown of CYLD in multiple models of PINK1 or parkin inactivation attenuates PARIS accumulation by modulating its ubiquitination levels and relieving its repressive effect on PGC-1α to promote mitochondrial biogenesis. Together, our studies identify CYLD as a negative regulator of dopamine neuron survival, and inhibition of CYLD may potentially be beneficial in PD by lowering PARIS levels and promoting mitochondrial biogenesis.

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Microglial activation in the dorsal striatum participates in anxiety-like behavior in Cyld knockout mice

Cited by 28 publications

References 79 publications

Deficiency of the CYLD Impairs Fear Memory of Mice and Disrupts Neuronal Activity and Synaptic Transmission in the Basolateral Amygdala

Deficiency of the CYLD Impairs Fear Memory of Mice and Disrupts Neuronal Activity and Synaptic Transmission in the Basolateral Amygdala

Cylindromatosis Drives Synapse Pruning and Weakening by Promoting Macroautophagy through Akt-mTOR Signaling

Deubiquitinase CYLD acts as a negative regulator of dopamine neuron survival in Parkinson’s disease

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