“Targeting astrocytes in CNS injury and disease: A translational research approach”

Filous, Angela R.; Silver, Jerry

doi:10.1016/j.pneurobio.2016.03.009

Cited by 136 publications

(112 citation statements)

References 252 publications

(279 reference statements)

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“…Any insult to astrocytes can disrupt the glutamate homeostasis that leads to glutamate excitotoxicity, which has been demonstrated in many neurodegenerative disorders, and implicated in some psychiatric disturbances in both humans and animal models (Rothstein et al, 1996; Reissner and Kalivas, 2010; Scofield and Kalivas, 2014; Filous and Silver, 2016). Studies in postmortem human depressed subjects and animal models of depression demonstrate reduced immunoreactivity of GFAP (GFAP-IR) and GLT-1 protein expression (Czeh et al, 2006; Banasr and Duman, 2008; Ye et al, 2011; Araya-Callis et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Disruption of the Glutamate–Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females

Rappeneau

Blaker

Petro

et al. 2016

Front. Behav. Neurosci.

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Background: Women are twice as likely as men to develop major depression. The brain mechanisms underlying this sex disparity are not clear. Disruption of the glutamate–glutamine cycle has been implicated in psychiatric disturbances. This study identifies sex-based impairments in the glutamate–glutamine cycle involving astrocytes using an animal model of depression.Methods: Male and female adult Long-Evans rats were exposed to chronic social defeat stress (CSDS) for 21 days, using a modified resident-intruder paradigm. Territorial aggression was used for males and maternal aggression was used for females to induce depressive-like deficits for intruders. The depressive-like phenotype was assessed with intake for saccharin solution, weight gain, estrous cycle, and corticosterone (CORT). Behaviors displayed by the intruders during daily encounters with residents were characterized. Rats with daily handling were used as controls for each sex. Ten days after the last encounter, both the intruders and controls were subjected to a no-net-flux in vivo microdialysis to assess glutamate accumulation and extracellular glutamine in the nucleus accumbens (NAc). The contralateral hemispheres were used for determining changes in astrocytic markers, including glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1).Results: Both male and female intruders reduced saccharin intake over the course of CSDS, compared to their pre-stress period and to their respective controls. Male intruders exhibited submissive/defensive behaviors to territorial aggression by receiving sideways threats and bites. These males showed reductions in striatal GLT-1 and spontaneous glutamine in the NAc, compared to controls. Female intruders exhibited isolated behaviors to maternal aggression, including immobility, rearing, and selfgrooming. Their non-reproductive days were extended. Also, they showed reductions in prefrontal and accumbal GFAP+ cells and prefrontal GLT-1, compared to controls. When 10 μM of glutamate was infused, these females showed a significant accumulation of glutamate compared to controls. Infusions of glutamate reduced extracellular glutamine for both male and female intruders compared to their respective controls.Conclusion: Twenty-one days of territorial or maternal aggression produced a depressive-like phenotype and impaired astrocytes in both male and female intruders. Disruption of the glutamate–glutamine cycle in the PFC-striatal network may be linked to depressive-like deficits more in females than in males.

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Section: Discussionmentioning

confidence: 99%

Disruption of the Glutamate–Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females

Rappeneau

Blaker

Petro

et al. 2016

Front. Behav. Neurosci.

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“…Astrocytes are known to have the ability to monitor neuronal activity and contribute to neurovascular coupling. On the one hand, astrocytes sense and respond to the metabolic changes of neurons via unknown mechanisms, possibly through glutamate signaling (Filous and Silver, 2016). On the other hand, the endfeet of astrocytes reach to pericytes and SMCs.…”

Section: Basics Of the Neurovascular Unit (Nvu)mentioning

confidence: 99%

Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect

Cai

Zhang

et al. 2017

Ageing Research Reviews

238

184

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Current understanding on the mechanisms of brain injury and neurodegeneration highlights an appreciation of multicellular interactions within the neurovascular unit (NVU), which include the evolution of blood-brain barrier (BBB) damage, neuronal cell death or degeneration, glial reaction, and immune cell infiltration. Aging is an important factor that influences the integrity of the NVU. The age-related physiological or pathological changes in the cellular components of the NVU have been shown to increase the vulnerability of the NVU to ischemia/reperfusion injury or neurodegeneration, and to result in deteriorated brain damage. This review describes the impacts of aging on each NVU component and discusses the mechanisms by which aging increases NVU sensitivity to stroke and neurodegenerative diseases. Prophylactic or therapeutic perspectives that may delay or diminish aging and thus prevent the incidence of these neurological disorders will also be reviewed.

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“…Other astrocytic functions which have been implicated in pathogenesis of HD are release of GABA, trophic factors, and inflammatory signaling (Filous and Silver, 2016). Astrocytes in HD models release less GABA, resulting in impaired tonic extra‐synaptic inhibition (Wojtowicz, Dvorzhak, Semtner, & Grantyn, 2013).…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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“Targeting astrocytes in CNS injury and disease: A translational research approach”

Cited by 136 publications

References 252 publications

Disruption of the Glutamate–Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females

Disruption of the Glutamate–Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females

Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

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