Astrocytes in Neuropathologies Affecting the Frontal Cortex

Peteri, Ulla-Kaisa; Niukkanen, Mikael; Castrén, Maija

doi:10.3389/fncel.2019.00044

Cited by 30 publications

(21 citation statements)

References 119 publications

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“…Besides their supportive role in terms of metabolism, astrocytes were shown to influence information processing and cognition by integrating local sensory information and behavioral state (Hallmann et al., 2017; Lima et al., 2014; Oksanen et al., 2019; Peteri et al., 2019; Slezak et al., 2019). In response to glucocorticoids, resetting of the circadian clock via non‐canonical pathways (Suchmanova et al., 2019) was reported.…”

Section: Discussionmentioning

confidence: 99%

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice

Nold

Richter

Hengerer

et al. 2020

Eur J of Neuroscience

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The brain is a central hub for integration of internal and external conditions and, thus, a regulator of the stress response. Glucocorticoids are the essential communicators of this response. Aberrations in glucocorticoid signaling are a common symptom in patients with psychiatric disorders. The gene FKBP5 encodes a chaperone protein that functionally inhibits glucocorticoid signaling and, thus, contributes to the regulation of stress. In the context of childhood trauma, differential expression of FKBP5 has been found in psychiatric patients compared to controls. These variations in expression levels of FKBP5 were reported to be associated with differences in stress responsiveness in human carriers of the single nucleotide polymorphism (SNP) rs1360780. Understanding the mechanisms underlying FKBP5 polymorphism‐associated glucocorticoid responsiveness in the CNS will lead to a better understanding of stress regulation or associated pathology. To study these mechanisms, two novel humanized mouse lines were generated. The lines carried either the risk (A/T) allele or the resilient (C/G) allele of rs1360780. Primary cells from CNS (astrocytes, microglia, and neurons) were analyzed for their basal expression levels of FKBP5 and their responsiveness to glucocorticoids. Differential expression of FKBP5 was found for these cell types and negatively correlated with the cellular glucocorticoid responsiveness. Astrocytes revealed the strongest transcriptional response, followed by microglia and neurons. Furthermore, the risk allele (A/T) was associated with greater induction of FKBP5 than the resilience allele. Novel FKBP5‐humanized mice display differential glucocorticoid responsiveness due to a single intronic SNP. The vulnerability to stress signaling in the shape of glucocorticoids in the brain correlated with FKBP5 expression levels. The strong responsiveness of astrocytes to glucocorticoids implies astrocytes play a prominent role in the stress response, and in FKBP5‐related differences in glucocorticoid signaling. The novel humanized mouse lines will allow for further study of the role that FKBP5 SNPs have in risk and resilience to stress pathology.

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Section: Discussionmentioning

confidence: 99%

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice

Nold

Richter

Hengerer

et al. 2020

Eur J of Neuroscience

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“…One of the most important astrocytes function is to deliver energy to neurons by the astrocyte-neuron lactate shuttle (Bass et al, 1971; Sherwood et al, 2006). Astrocytes modulate Ca 2+ variations that influence neuronal activity releasing gliotransmitters (Peteri et al, 2019). The modulation of the neurotransmitter uptake involves the excitatory transporters 1 and 2 (EAAT1 and 2) (Roberts et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Astrocytes: Role and Functions in Brain Pathologies

2019

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Astrocytes are a population of cells with distinctive morphological and functional characteristics that differ within specific areas of the brain. Postnatally, astrocyte progenitors migrate to reach their brain area and related properties. They have a regulatory role of brain functions that are implicated in neurogenesis and synaptogenesis, controlling blood–brain barrier permeability and maintaining extracellular homeostasis. Mature astrocytes also express some genes enriched in cell progenitors, suggesting they can retain proliferative potential. Considering heterogeneity of cell population, it is not surprising that their disorders are related to a wide range of different neuro-pathologies. Brain diseases are characterized by the active inflammatory state of the astrocytes, which is usually described as up-regulation of glial fibrillary acidic protein (GFAP). In particular, the loss of astrocytes function as a result of cellular senescence could have implications for the neurodegenerative disorders, such as Alzheimer disease and Huntington disease, and for the aging brain. Astrocytes can also drive the induction and the progression of the inflammatory state due to their Ca2+ signals and that it is strongly related to the disease severity/state. Moreover, they contribute to the altered neuronal activity in several frontal cortex pathologies such as ischemic stroke and epilepsy. There, we describe the current knowledge pertaining to astrocytes’ role in brain pathologies and discuss the possibilities to target them as approach toward pharmacological therapies for neuro-pathologies.

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“…It is well established that occurrence of a traumatic event during adolescence [ 4 , 15 ], as well as developmental changes that occur during that stage [ 4 ], might increase the risk for PTSD and ADHD, where DA homeostasis has been shown to be altered [ 16 , 17 ]. Enhanced inflammatory conditions [ 18 ] and neurodegenerative hallmarks related to DAT alterations [ 19 , 20 , 21 ] are among the most relevant underlying mechanisms of aberrant PFC function in these disorders. Recent studies have also shown the important role played by astrocytes in the control of DA homeostasis in the PFC during early adolescence [ 13 , 19 ], when glutamatergic synapses in this area are at an important maturational stage [ 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Early Adolescence Prefrontal Cortex Alterations in Female Rats Lacking Dopamine Transporter

et al. 2021

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Monoamine dysfunctions in the prefrontal cortex (PFC) can contribute to diverse neuropsychiatric disorders, including ADHD, bipolar disorder, PTSD and depression. Disrupted dopamine (DA) homeostasis, and more specifically dopamine transporter (DAT) alterations, have been reported in a variety of psychiatric and neurodegenerative disorders. Recent studies using female adult rats heterozygous (DAT+/−) and homozygous (DAT−/−) for DAT gene, showed the utility of those rats in the study of PTSD and ADHD. Currently, a gap in the knowledge of these disorders affecting adolescent females still represents a major limit for the development of appropriate treatments. The present work focuses on the characterization of the PFC function under conditions of heterozygous and homozygous ablation of DAT during early adolescence based on the known implication of DAT and PFC DA in psychopathology during adolescence. We report herein that genetic ablation of DAT in the early adolescent PFC of female rats leads to changes in neuronal and glial cell homeostasis. In brief, we observed a concurrent hyperactive phenotype, accompanied by PFC alterations in glutamatergic neurotransmission, signs of neurodegeneration and glial activation in DAT-ablated rats. The present study provides further understanding of underlying neuroinflammatory pathological processes that occur in DAT-ablated female rats, what can provide novel investigational approaches in human diseases.

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Astrocytes in Neuropathologies Affecting the Frontal Cortex

Cited by 30 publications

References 119 publications

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice

Astrocytes: Role and Functions in Brain Pathologies

Early Adolescence Prefrontal Cortex Alterations in Female Rats Lacking Dopamine Transporter

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