Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice

Fan, Ze; Zhang, Zhihao; Zhao, Shuang; Zhu, Yuanyuan; Guo, Dong; Yang, Bo; Zhuo, Lixia; Han, Junying; Wang, Rui; Fang, Zongping; Dong, Hailong; Li, Yan; Xiong, Lize

doi:10.1007/s12264-020-00587-3

Cited by 8 publications

(8 citation statements)

References 55 publications

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“…No significant difference was recorded between total and soluble cortical glycogen in WT mice (Figure 2(b)), suggesting that most glycogen ($88%) is readily accessible in its soluble form. Of note, and as expected, total cortical and cerebellar glycogen contents in WT mice were respectively one-and two-orders of magnitude lower than that of the glycogen-rich organs skeletal muscle and liver 52 and consistent with several other studies, [53][54][55][56] but lower than the highest reported values 57 (Table S1).…”

Section: Defective Brain Glycophagy In Wdfy3 þ/Lacz Micesupporting

confidence: 92%

Wdfy3 regulates glycophagy, mitophagy, and synaptic plasticity

Napoli

Πανουτσόπουλος

Kysar

et al. 2021

J Cereb Blood Flow Metab

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Autophagy is essential to cell function, as it enables the recycling of intracellular constituents during starvation and in addition functions as a quality control mechanism by eliminating spent organelles and proteins that could cause cellular damage if not properly removed. Recently, we reported on Wdfy3’s role in mitophagy, a clinically relevant macroautophagic scaffold protein that is linked to intellectual disability, neurodevelopmental delay, and autism spectrum disorder. In this study, we confirm our previous report that Wdfy3 haploinsufficiency in mice results in decreased mitophagy with accumulation of mitochondria with altered morphology, but expanding on that observation, we also note decreased mitochondrial localization at synaptic terminals and decreased synaptic density, which may contribute to altered synaptic plasticity. These changes are accompanied by defective elimination of glycogen particles and a shift to increased glycogen synthesis over glycogenolysis and glycophagy. This imbalance leads to an age-dependent higher incidence of brain glycogen deposits with cerebellar hypoplasia. Our results support and further extend Wdfy3’s role in modulating both brain bioenergetics and synaptic plasticity by including glycogen as a target of macroautophagic degradation.

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Section: Defective Brain Glycophagy In Wdfy3 þ/Lacz Micesupporting

confidence: 92%

Wdfy3 regulates glycophagy, mitophagy, and synaptic plasticity

Napoli

Πανουτσόπουλος

Kysar

et al. 2021

J Cereb Blood Flow Metab

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“…To assess whether depression can be alleviated by enhancing glycogenolysis at the gene level, we used an astrocyte-specific PYGB over-expression (KI-Pygb) mouse model ( Cai et al, 2020 ). As previously reported ( Fan et al, 2020 ), homozygous Pygb H 11/ H 11 mice and WT littermate genotypes were identified by PCR ( Figure 4A ). PYGB and phosphorylated PYGB protein levels were increased in homozygous Pygb H 11/ H 11 mice when compared with WT littermate controls ( Fan et al, 2020 ).…”

Section: Resultssupporting

confidence: 76%

“…As previously reported ( Fan et al, 2020 ), homozygous Pygb H 11/ H 11 mice and WT littermate genotypes were identified by PCR ( Figure 4A ). PYGB and phosphorylated PYGB protein levels were increased in homozygous Pygb H 11/ H 11 mice when compared with WT littermate controls ( Fan et al, 2020 ). Behavioral analyses were performed in the CD1 attack period, according to the timeline shown in Figure 4B .…”

Section: Resultssupporting

confidence: 76%

“…In addition, we injected AAV containing the astrocyte-specific GFAP promoter targeting the PYGB gene, which restricts the expression of astrocytes in the mPFC region for 4 weeks before mice performed a series of behavioral tests ( Figure 5A ). The knock down efficiency of PYGB verification was shown in previous studies, which demonstrated a significant increase in the glycogen level compared to control ( Cai et al, 2020 ; Fan et al, 2020 ). The knockdown efficiency in vivo was confirmed by immunofluorescence staining and Western blot.…”

Section: Resultssupporting

confidence: 69%

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Brain-Type Glycogen Phosphorylase Is Crucial for Astrocytic Glycogen Accumulation in Chronic Social Defeat Stress-Induced Depression in Mice

Zhu

Fan

Zhao

et al. 2022

Front. Mol. Neurosci.

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Astrocytic glycogen plays an important role in brain energy metabolism. However, the contribution of glycogen metabolism to stress-induced depression remains unclear. Chronic social defeat stress was used to induce depression-like behaviors in mice, assessed with behavioral tests. Glycogen concentration in the medial prefrontal cortex (mPFC) and the expression of key enzymes of the glycogen metabolism were investigated using Western blots, immunofluorescent staining, electron microscopy, and biochemical assays. Stereotaxic surgery and viral-mediated gene transfer were applied to knockdown or overexpress brain-type glycogen phosphorylase (PYGB) in the mPFC. The glycogen content increased in the mPFC after stress. Glycogenolytic dysfunction due to inactivation of PYGB was responsible for glycogen accumulation. Behavioral tests on astrocyte-specific PYGB overexpression mice showed that augmenting astrocytic PYGB reduces susceptibility to depression when compared with stress-susceptible mice. Conversely, PYGB genetic down-regulation in the mPFC was sufficient to induce glycogen accumulation and depression-like behaviors. Furthermore, PYGB overexpression in the mPFC decreases susceptibility to depression, at least partially by rescuing glycogen phosphorylase activity to maintain glycogen metabolism homeostasis during stress. These findings indicate that (1) glycogen accumulation occurs in mice following stress and (2) glycogenolysis reprogramming leads to glycogen accumulation in astrocytes and PYGB contributes to stress-induced depression-like behaviors. Pharmacological tools acting on glycogenolysis might constitute a promising therapy for depression.

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“…Further related to the glucose metabolism, another feature that is peculiar to astroglial cells (although not exclusive) is the glycogen storage, which can be mobilised in the events of increased energy demand and during brain repair [97,221]. The evidence for this is based on the observations that glycogen levels in the brain are increased when neuronal activity is inhibited (e.g., under general anaesthesia) [227]. Moreover, reactive astrocytes in the vicinity of damaged neuropil exhibit the increased accumulation of glycogen [228], which is interesting in view of the upregulation in astroglial GLP-1 receptor expression following ischaemic injury, as mentioned above [218].…”

Section: Effects Of Glp1-ras At the Nvumentioning

confidence: 99%

GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight

Monti

Moreira

Richner

et al. 2022

Cells

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Defects in brain energy metabolism and proteopathic stress are implicated in age-related degenerative neuronopathies, exemplified by Alzheimer’s disease (AD) and Parkinson’s disease (PD). As the currently available drug regimens largely aim to mitigate cognitive decline and/or motor symptoms, there is a dire need for mechanism-based therapies that can be used to improve neuronal function and potentially slow down the underlying disease processes. In this context, a new class of pharmacological agents that achieve improved glycaemic control via the glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular and animal models of AD and PD, has been discussed in several research reports and review opinions recently. In this review article, we discuss the pathological relevance of derangements in the neurovascular unit and the significance of neuron–glia metabolic coupling in AD and PD. With this context, we also discuss some unresolved questions with regard to the potential benefits of GLP-1 agonists on the neurovascular unit (NVU), and provide examples of novel experimental paradigms that could be useful in improving our understanding regarding the neuroprotective mode of action associated with these agents.

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Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice

Cited by 8 publications

References 55 publications

Wdfy3 regulates glycophagy, mitophagy, and synaptic plasticity

Wdfy3 regulates glycophagy, mitophagy, and synaptic plasticity

Brain-Type Glycogen Phosphorylase Is Crucial for Astrocytic Glycogen Accumulation in Chronic Social Defeat Stress-Induced Depression in Mice

GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight

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