Astrocyte-Derived Lactate Modulates the Passive Coping Response to Behavioral Challenge in Male Mice

Yin, Yanan; Hu, Jian; Yi-li, Wei; Li, Zelin; Luo, Zhaoming; Wang, Ruiqi; Yang, Kexin; Li, Shu-Ji; Li, Xiaowen; Yang, Jian‐Ming; Gao, Tianming

doi:10.1007/s12264-020-00553-z

Cited by 28 publications

(14 citation statements)

References 78 publications

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“…In addition to the hippocampus, MCT4 has been shown to play an important role in modulating hypothalamus-related behaviors, including feeding behaviors (Portela et al, 2017). Similar to our findings in the M1 primary motor cortex, MCT4 has also been shown to play a role in neuroplasticity of other cortical brain regions, including the prefrontal cortex, where knockdown of MCT4 led to loss of a passive coping response following stress exposure (Yin et al, 2021). To the best of our knowledge our study is the first to demonstrate the potential role of MCT4 in mediating motor learning behaviors of the M1 primary motor cortex.…”

Section: Discussionsupporting

confidence: 85%

“…For example, genetic knockdown of the ANLS has been repeatedly shown to impair long-term potentiation and dendritic spine density as well as spatial memory acquisition and consolidation in the rodent brain (Harris et al, 2019;Netzahualcoyotzi & Pellerin, 2020;Suzuki et al, 2011;Vezzoli et al, 2020). A more recent study has also shown that the ANLS plays a role in the prefrontal cortex, with knockdown of MCT4 resulting in a loss of a stress-induced coping response (Yin et al, 2021). However, a major gap in knowledge is the role of MCT4 and the ANLS in mediating neuroplasticity of other cortical brain regions, including the M1 primary motor cortex.…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of astrocytic monocarboxylate transporter 4 (MCT4) in the motor cortex leads to loss of dendritic spines and a deficit in motor learning

Lundquist

Llewellyn

Kishi

et al. 2021

Preprint

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Monocarboxylate transporters (MCTs) shuttle molecules, including L-lactate, involved in metabolism and cell signaling of the central nervous system. Astrocyte-specific MCT4 is a key component of the astrocyte-neuron lactate shuttle (ANLS) and is important for neuroplasticity and learning of the hippocampus. However, the importance of astrocyte-specific MCT4 in neuroplasticity of the M1 primary motor cortex remains unknown. In this study, we investigated astrocyte-specific MCT4 in motor learning and neuroplasticity of the M1 primary motor cortex using a cell-type specific shRNA knockdown of MCT4. Knockdown of astrocyte-specific MCT4 resulted in impaired motor performance and learning on the accelerating rotarod. In addition, MCT4 knockdown was associated with a reduction of neuronal dendritic spine density and spine width and decreased protein expression of PSD95 and Arc. Using near-infrared-conjugated 2-deoxyglucose uptake as a surrogate marker for neuronal activity, MCT4 knockdown was also associated with decreased neuronal activity in the M1 primary motor cortex and associated motor regions including the dorsal striatum and ventral thalamus. Our study supports a potential role for astrocyte-specific MCT4 and the ANLS in the neuroplasticity of the M1 primary motor cortex. Targeting MCT4 may serve to enhance neuroplasticity and motor repair in several neurological disorders, including Parkinson's disease and stroke.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Knockdown of astrocytic monocarboxylate transporter 4 (MCT4) in the motor cortex leads to loss of dendritic spines and a deficit in motor learning

Lundquist

Llewellyn

Kishi

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Astrocytes can release a variety of synaptic transmitters and modulators, including but not limited to glutamate, D-serine, ATP/adenosine, GABA and lactate through calcium-dependent and -independent signaling pathways [52][53][54][55] . We found that not all gliotransmitters were affected equally in IP3R2 mutant mice; instead, only ATP deficiency was observed in the absence of IP3R2, consistent with past work 56 .…”

Section: Discussionmentioning

confidence: 99%

Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice

Wang

Kong

et al. 2021

Nat Commun

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Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca2+ release from intracellular Ca2+ stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD.

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“…Clemastine was prepared freshly each day by dissolving the powder in normal saline. The selected dose is based on previous studies, which proves that clemastine has the effect of enhancing cognition and remyelination ( Li et al, 2019 ; Chen et al, 2021b ; Li et al, 2021 ). Aged mice in the CON and PND group received an intraperitoneal injection of the same amount of normal saline every day to ensure the consistency of the experiment.…”

Section: Methodsmentioning

confidence: 99%

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

Zhang

Zhou

et al. 2021

Front. Pharmacol.

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Perioperative neurocognitive disorder (PND) leads to progressive deterioration of cognitive function, especially in aged patients. Demyelination is closely associated with cognitive dysfunction. However, the relationship between PND and demyelination remains unclear. Here we showed that demyelination was related to the pathogenesis of PND. Clemastine, an antihistamine with potency in remyelination, was predicted to have a potential therapeutic effect on PND by next-generation sequencing and bioinformatics in our previous study. In the present study, it was given at 10 mg/kg per day for 2 weeks to evaluate the effects on PND in aged mice. We found that clemastine ameliorated PND and reduced the expression levels of inflammatory factors such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Further investigation suggested clemastine increased the expression of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP) to enhance remyelination by inhibiting the overactivation of the WNT/β-catenin pathway. At the same time, the expression of post-synaptic density protein 95 (PSD95, or DLG4), brain-derived neurotrophic factor (BDNF), synaptosomal-associated protein 25 (SNAP25) and neuronal nuclei (NEUN) were also improved. Our results suggested that clemastine might be a therapy for PND caused by anesthetic and surgical factors in aged patients.

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Astrocyte-Derived Lactate Modulates the Passive Coping Response to Behavioral Challenge in Male Mice

Cited by 28 publications

References 78 publications

Knockdown of astrocytic monocarboxylate transporter 4 (MCT4) in the motor cortex leads to loss of dendritic spines and a deficit in motor learning

Knockdown of astrocytic monocarboxylate transporter 4 (MCT4) in the motor cortex leads to loss of dendritic spines and a deficit in motor learning

Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

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