P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice

Garré, Juan Mauricio; Silva, Hernandez Moura; Lafaille, Juan J.; Yang, Guang

doi:10.1038/s41467-020-15590-5

Cited by 28 publications

(23 citation statements)

References 70 publications

(95 reference statements)

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“…Besides autoimmune diseases, increased basal spine turnover has been observed in many inflammatory conditions where central and/or peripheral immune responses are evoked by lipopolysaccharides (Kondo et al, 2011), viral mimic (Garre et al, 2017), or craniotomy (Xu et al, 2007). In a mouse model of Rett syndrome, MECP2 deficiency leads to the recruitment of inflammatory myeloid cells into the cortex and greater spine elimination and formation in frontal cortical pyramidal neurons (Garre et al, 2020). Collectively, these findings highlight the potent effect of immune responses on destabilizing neuronal network connections.…”

Section: Discussionmentioning

confidence: 94%

Learning‐dependent dendritic spine plasticity is impaired in spontaneous autoimmune encephalomyelitis

Huang

Lafaille

Yang

2021

Developmental Neurobiology

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Multiple sclerosis (MS) is thought to be an autoimmune disease and is pathologically characterized by immune cell infiltration, demyelination, and axonal damage in the central nervous system (CNS) (Milo & Kahana, 2010). The major symptoms of MS include motor dysfunction, depression, sensory disabilities, and cognitive impairment. Experimental autoimmune encephalomyelitis (EAE) has long been used as an animal model of MS, recapitulating the main pathological features of human disease. Like MS, EAE has a strong autoimmune component. After immunization of mice with CNS myelin antigens, such as myelin basic protein (MBP), proteolipid protein, and myelin oligodendrocyte glycoprotein (MOG), self-reactive CD4 + T cells cross the blood-brain barrier and recruit peripheral immune cells into the CNS (Hickey et al., 1991;Kim et al., 2010;Ransohoff et al., 2003). The perpetuation of inflammatory response in the CNS leads to demyelination, cell death, and motor symptoms.Before the onset of motor dysfunction, EAE mice exhibit a range of sensory, emotional, and cognitive changes including learning and memory impairments at the early stages of the

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Section: Discussionmentioning

confidence: 94%

Learning‐dependent dendritic spine plasticity is impaired in spontaneous autoimmune encephalomyelitis

Huang

Lafaille

Yang

2021

Developmental Neurobiology

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“…These observations are highly pertinent to Rett neuropathology, as Mecp2 mutations are associated with impairments in locomotion and motor skill learning, which directly relates to the functionality of striatal motor control. Similarly, Mecp2 mutant mice show respiratory problems, including dysrhythmia and apnea, which are attributed to the malfunctioning/hyperexcitability of the pons [41,42]. Interestingly, SEMA4D levels were somewhat reduced in neurons of Mecp2 T158A/y mice following treatment.…”

Section: Discussionmentioning

confidence: 99%

“…MeCP2 deficiencies have been reported to alter immune responses and interactions between lymphocytes and myeloid cells [4]. Iba1+ cells at the cortical border may represent non-microglial myeloid cells [41], however, ramified Iba1+ cells deep within the striatum are likely to be microglia whose reduced process complexity is indicative of activation in the Mecp2 T158A/y mice [4]. Detailed mechanistic studies are required to characterise and further investigate how the Mecp2 mutations affect Plexin B1 expression in glial cells, and effects of SEMA4D on neuronal function and phenotype, as well as the impact on peripheral immune responses that can also influence neuropathology of Rett syndrome.…”

Section: Discussionmentioning

confidence: 99%

Anti-Semaphorin 4D Rescues Motor, Cognitive, and Respiratory Phenotypes in a Rett Syndrome Mouse Model

Mao

Evans

Mishra

et al. 2021

IJMS

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Rett syndrome is a neurodevelopmental disorder caused by mutations of the methyl-CpG binding protein 2 gene. Abnormal physiological functions of glial cells contribute to pathogenesis of Rett syndrome. Semaphorin 4D (SEMA4D) regulates processes central to neuroinflammation and neurodegeneration including cytoskeletal structures required for process extension, communication, and migration of glial cells. Blocking SEMA4D-induced gliosis may preserve normal glial and neuronal function and rescue neurological dysfunction in Rett syndrome. We evaluated the pre-clinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody in the Rett syndrome Mecp2T158A transgenic mouse model and investigated the contribution of glial cells as a proposed mechanism of action in treated mice and in primary glial cultures isolated from Mecp2T158A/y mutant mice. SEMA4D is upregulated in neurons while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1-positive cells are upregulated in Mecp2T158A/y mice. Anti-SEMA4D treatment ameliorates Rett syndrome-specific symptoms and improves behavioural functions in both pre-symptomatic and symptomatic cohorts of hemizygous Mecp2T158A/y male mice. Anti-SEMA4D also reduces astrocyte and microglia activation in vivo. In vitro experiments demonstrate an abnormal cytoskeletal structure in mutant astrocytes in the presence of SEMA4D, while anti-SEMA4D antibody treatment blocks SEMA4D–Plexin B1 signaling and mitigates these abnormalities. These results suggest that anti-SEMA4D immunotherapy may be an effective treatment option to alleviate symptoms and improve cognitive and motor function in Rett syndrome.

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“…Large numbers of Ca 2+ influx activate a variety of downstream cell signal transduction pathways that excite nociceptive neurons, thereby increasing their excitability and resulting in pain sensation [59,61,62]. Rett syndrome (RTT), an early-onset neurodevelopmental disorder, resulted in accumulation of P2X7R-expressing monocytes and macrophages located at the edge of the cerebral cortex, while P2X7R deficiency or pharmacological block restored cortical dendritic spine plasticity, and ameliorated social behavioral defects of RTT mice [63].…”

Section: Ivyspringmentioning

confidence: 99%

PRG-1 relieves pain and depressive-like behaviors in rats of bone cancer pain by regulation of dendritic spine in hippocampus

Liu¹,

Xie²,

Li³

et al. 2021

Int. J. Biol. Sci.

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Rationale: Pain and depression, which tend to occur simultaneously and share some common neural circuits and neurotransmitters, are highly prevalent complication in patients with advanced cancer. Exploring the underlying mechanisms is the cornerstone to prevent the comorbidity of chronic pain and depression in cancer patients. Plasticity-related gene 1 (PRG-1) protein regulates synaptic plasticity and brain functional reorganization during neuronal development or after cerebral lesion. Purinergic P2X7 receptor has been proposed as a therapeutic target for various pain and neurological disorders like depression in rodents. In this study, we investigated the roles of PRG-1 in the hippocampus in the comorbidity of pain and depressive-like behaviors in rats with bone cancer pain (BCP). Methods: The bone cancer pain rat model was established by intra-tibial cell inoculation of SHZ-88 mammary gland carcinoma cells. The animal pain behaviors were assessed by measuring the thermal withdrawal latency values by using radiant heat stimulation and mechanical withdrawal threshold by using electronic von Frey anesthesiometer, and depressive-like behavior was assessed by sucrose preference test and forced swim test. Alterations in the expression levels of PRG-1 and P2X7 receptor in hippocampus were separately detected by using western blot, immunofluorescence and immunohistochemistry analysis. The effects of intra-hippocampal injection of FTY720 (a PRG-1/PP2A interaction activator), PRG-1 overexpression or intra-hippocampal injection of A438079 (a selective competitive P2X7 receptor antagonist) were also observed. Results: Carcinoma intra-tibia injection caused thermal hyperalgesia, mechanical allodynia and depressive-like behaviors in rats, and also induced the deactivation of neurons and dendritic spine structural anomalies in the hippocampus. Western blot, immunofluorescence and immunohistochemistry analysis showed an increased expression of PRG-1 and P2X7 receptor in the hippocampus of BCP rats. Intra-hippocampal injection of FTY720 or A438079 attenuated both pain and depressive-like behaviors. Furthermore, overexpression of PRG-1 in hippocampus has similar analgesic efficacy to FTY720. In addition, they rescued neuron deactivation and dendritic spine anomalies. Conclusion:The results suggest that both PRG-1 and P2X7 receptor in the hippocampus play important roles in the development of pain and depressive-like behaviors in bone cancer condition in rats by dendritic spine regulation via P2X7R/PRG-1/PP2A pathway.

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P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice

Cited by 28 publications

References 70 publications

Learning‐dependent dendritic spine plasticity is impaired in spontaneous autoimmune encephalomyelitis

Learning‐dependent dendritic spine plasticity is impaired in spontaneous autoimmune encephalomyelitis

Anti-Semaphorin 4D Rescues Motor, Cognitive, and Respiratory Phenotypes in a Rett Syndrome Mouse Model

PRG-1 relieves pain and depressive-like behaviors in rats of bone cancer pain by regulation of dendritic spine in hippocampus

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