Elevated Level of PKMζ Underlies the Excessive Anxiety in an Autism Model

Gao, Xiaoli; Zheng, Rui; Ma, Xiaoyan; Gong, Zhiting; Xia, Dan; Zhou, Qiang

doi:10.3389/fnmol.2019.00291

Cited by 15 publications

(19 citation statements)

References 41 publications

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“…Data with AMN082 would suggest the use of mGluR7 receptor agonists for treating anxiety (Spooren et al, 2010;Cieślik et al, 2018). Anxiety level is significantly higher in VPA-injected and BTBR mice (Gao et al, 2019;Queen et al, 2020). In agreement with previous results, we found overexpression of mGluR7 alleviates their anxiety-like traits.…”

Section: Discussionsupporting

confidence: 91%

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Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

Wang

Gao

Zhang

et al. 2021

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) is associated with a range of abnormalities pertaining to socialization, communication, repetitive behaviors, and restricted interests. Owing to its complexity, the etiology of ASD remains incompletely understood. The presynaptic G protein-coupled glutamate receptor metabotropic glutamate receptor 7 (mGluR7) is known to be essential for synaptic transmission and is also tightly linked with ASD incidence. Herein, we report that prefrontal cortex (PFC) mGluR7 protein levels were decreased in C57BL/6J mice exposed to valproic acid (VPA) and BTBR T+ Itpr3tf/J mice. The overexpression of mGluR7 in the PFC of these mice using a lentiviral vector was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, anxiety-like, and stereotyped/repetitive behaviors. Intriguingly, patch-clamp recordings revealed that the overexpression of mGluR7 suppressed neuronal excitability by inhibiting action potential discharge frequencies, together with enhanced action potential threshold and increased rheobase. These data offer a scientific basis for the additional study of mGluR7 as a promising therapeutic target in ASD and related neurodevelopmental disorders.

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Section: Discussionsupporting

confidence: 91%

“…Stereotype and behavior rigidity are widely known as core and defining features of ASD (Gilbert and O'Connor, 2020). Many lines of evidence have shown that VPA-treated and BTBR mice exhibited the increase in marble burying (Amodeo et al, 2012(Amodeo et al, , 2014Baronio et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

Wang

Gao

Zhang

et al. 2021

Front. Cell. Neurosci.

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“…Western Blot. As our previously described ( Gao et al, 2019 ), tissues were collected, homogenized in RIPA buffer (Beyotime Biotechnology, China) containing 1 mM PMSF (Sigma), 25 μM leupeptin (Sigma), and 1 μg/ml aprotinin (Sigma), and centrifuged at 4°C for 0.5 h at 10,000 g, with the supernatant collected. Total protein lysates made from hippocampus or entire brain were mixed with SDS gel-loading buffer and heated for 5 min at 100°C.…”

Section: Methodsmentioning

confidence: 99%

Xueshuantong Improves Functions of Lymphatic Ducts and Modulates Inflammatory Responses in Alzheimer’s Disease Mice

2021

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Recent studies have revealed significant contributions of lymphatic vessels (LVs) to vital functions of the brain, especially related to clearance of waste from the brain and immune responses in the brain. These studies collectively indicate that enhancing the functions of LVs may improve brain functions during brain aging and in Alzheimer’s disease (AD) where LV functions are impaired. However, it is currently unknown whether this enhancement can be achieved using small molecules. We have previously shown that a widely used Chinese herbal medicine Xueshuantong (XST) significantly improves functions and reduces pathology in AD transgenic mice associated with elevated cerebral blood flow (CBF). Here, we show that XST partially rescues deficits in lymphatic structures, improves clearance of amyloid-β (Aβ) from the brain, and reduces the inflammatory responses in the serum and brains of transgenic AD mice. In addition, we showed that this improvement in the lymphatic system occurs independently of elevated CBF, suggesting independent modulation and limited interaction between blood circulation and lymphatic systems. Moreover, XST treatment leads to a significant increase in GLT-1 level and a significantly lower level of MMP-9 and restores AQP4 polarity in APP/PS1 mice. These results provide the basis for further exploration of XST to enhance or restore LV functions, which may be beneficial to treat neurodegenerative diseases or promote healthy aging.

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“…ICR mice were housed and fed at Peking University Shenzhen Graduate School as our previous study did (Gao et al, 2019). All experiments have been approved by the Peking University Shenzhen Graduate School Animal Care and Use Committee and were performed following the ARRIVE guidelines on the Care and Use of Experimental Animals.…”

Section: Animalsmentioning

confidence: 99%

“…Brain tissue processing was performed based on previously published methods (Donato et al, 2015;Gao et al, 2019). In brief, upon removal, whole brains were fixed overnight in 4% paraformaldehyde at 4 • C, followed by cryoprotection with 30% sucrose for 48 h. Brains were then paraffin-embedded and sectioned at 40 µm on a cryostat (Leica CM1860 UV, Germany).…”

Section: Brain Tissue Processing and Immunostainingmentioning

confidence: 99%

Altered Relationship Between Parvalbumin and Perineuronal Nets in an Autism Model

Xia

Yang

et al. 2021

Front. Mol. Neurosci.

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Altered function or presence of inhibitory neurons is documented in autism spectrum disorders (ASD), but the mechanism underlying this alternation is poorly understood. One major subtype of inhibitory neurons altered is the parvalbumin (PV)-containing neurons with reduced density and intensity in ASD patients and model mice. A subpopulation of PV+ neurons expresses perineuronal nets (PNN). To better understand whether the relationship between PV and PNN is altered in ASD, we measured quantitatively the intensities of PV and PNN in single PV+ neurons in the prelimbic prefrontal cortex (PrL-PFC) of a valproic acid (VPA) model of ASD at different ages. We found a decreased PV intensity but increased PNN intensity in VPA mice. The relationship between PV and PNN intensities is altered in VPA mice, likely due to an “abnormal” subpopulation of neurons with an altered PV-PNN relationship. Furthermore, reducing PNN level using in vivo injection of chondroitinase ABC corrects the PV expression in adult VPA mice. We suggest that the interaction between PV and PNN is disrupted in PV+ neurons in VPA mice which may contribute to the pathology in ASD.

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Elevated Level of PKMζ Underlies the Excessive Anxiety in an Autism Model

Cited by 15 publications

References 41 publications

Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

Xueshuantong Improves Functions of Lymphatic Ducts and Modulates Inflammatory Responses in Alzheimer’s Disease Mice

Altered Relationship Between Parvalbumin and Perineuronal Nets in an Autism Model

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