Astrocyte-Derived Thrombospondin Induces Cortical Synaptogenesis in a Sex-Specific Manner

Mazur, Anna; Bills, Ean H.; Deschepper, Kayla; Williamson, James C; Henderson, Brandon J.; Risher, W. Christopher

doi:10.1523/eneuro.0014-21.2021

Cited by 18 publications

(17 citation statements)

References 55 publications

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“…Several publications have reported the existence of sexual differences as a global feature of brain functioning (Alshammari, 2021; Berchtold et al, 2008; Cieri et al, 2022; del Mauro et al, 2022; Guebel et al, 2016; Mazur et al, 2021; Pallayova et al, 2019; Taylor et al, 2021; Yang et al, 2021). Therefore, herein it was tested whether this phenomenon also occurs in the astrocytic population.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, the systematic characterization of numerous differential astrocytic features linked to sex was notably possible (Sections 3.4 and 3.5). The occurrence of sexual differences in astrocytes is relevant because this feature has often been ignored even when individuals of both sexes were included in the studies (Chai et al, 2017;Lanke et al, 2018), or sex differences was sought, but only in relation to a unique molecule (Johnson et al, 2008;Lennol et al, 2021;Mazur et al, 2021;Morrison & Filosa, 2016;Sanfilippo et al, 2019Sanfilippo et al, , 2020Santos-Galindo et al, 2011;Taylor et al, 2021). An exception is the work of Krawczyk et al (2022) who investigated sexual differences in human cortical astrocytes at a general level, but in a tumoural environment.…”

Section: Discussionmentioning

confidence: 99%

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Human hippocampal astrocytes: Computational dissection of their transcriptome, sexual differences and exosomes across ageing and mild‐cognitive impairment

Guebel¹

2023

Eur J of Neuroscience

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The role of astrocytes in Alzheimer's disease is often disregarded. Hence, characterization of astrocytes along their early evolution toward Alzheimer would be greatly beneficial. However, due to their exquisite responsiveness, in vivo studies are difficult. So public microarray data of hippocampal homogenates from (healthy) young, (healthy) elder and elder with mild cognitive impairment (MCI) were subjected to re‐analysis by a multi‐step computational pipeline. Ontologies and pathway analyses were compared after determining the differential genes that, belonging to astrocytes, have splice forms. Likewise, the subset of molecules exportable to exosomes was also determined. The results showed that astrocyte's phenotypes changed significantly. While already ‘activated’ astrocytes were found in the younger group, major changes occurred during ageing (increased vascular remodelling and response to mechanical stimulus, diminished long‐term potentiation and increased long‐term depression). MCI's astrocytes showed some ‘rejuvenated’ features, but their sensitivity to shear stress was markedly lost. Importantly, most of the changes showed to be sex biassed. Men's astrocytes are enriched in a type ‘endfeet‐astrocytome’, whereas women's astrocytes appear close to the ‘scar‐forming’ type (prone to endothelial dysfunction, hypercholesterolemia, loss of glutamatergic synapses, Ca+2 dysregulation, hypoxia, oxidative stress and ‘pro‐coagulant’ phenotype). In conclusion, the computational dissection of the networks based on the hippocampal gene isoforms provides a relevant proxy to in vivo astrocytes, also revealing the occurrence of sexual differences. Analyses of the astrocytic exosomes did not provide an acceptable approximation to the overall functioning of astrocytes in the hippocampus, probably due to the selective cellular mechanisms which charge the cargo molecules.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human hippocampal astrocytes: Computational dissection of their transcriptome, sexual differences and exosomes across ageing and mild‐cognitive impairment

Guebel¹

2023

Eur J of Neuroscience

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“…To determine the effect of acute opioid exposure on synapse formation during the peak synaptogenic window for rodent CNS [34,35], we purified neurons and astrocytes from the cortices of male P0-1 rat pups (Figure 1A). Only male pups were used due to our previous finding that, at least in rats, astrocytemediated synaptic development demonstrates significant sex differences, with male-derived neurons showing a significantly greater response to astrocyte-secreted factors than those from females [29]. Neurons were cultured in either the presence or absence of astrocyte inserts (allowing the cells to share media and thus secreted factors) followed by acute treatment with buprenorphine.…”

Section: Acute Buprenorphine Exposure Inhibits Astrocyte-mediated Syn...mentioning

confidence: 99%

“…Cortical astrocytes were purified separately from either male P1 Sprague-Dawley rats (no prenatal drug exposure) or mixed sex P1 C57Bl/6J mice (prenatally exposed to either buprenorphine or vehicle control) following a similar protocol to neurons, as described above [29]. After the Nitex mesh filtering step, the cell solution was centrifuged and the pellet resuspended in astrocyte growth media [AGM; DMEM + GlutaMax (Gibco), 10% heat-inactivated fetal bovine serum (FBS; MilliporeSigma), 10 µM hydrocortisone (MilliporeSigma), 100 U/mL Pen/Strep (Gibco), 5 µg/mL Insulin (Sigma), 1 mM NaPyruvate (Gibco), 5 µg/mL N-Acetyl-L-cysteine (NAC; MilliporeSigma)].…”

Section: Cortical Astrocyte Purification Culture Transfection and Lysismentioning

confidence: 99%

Abnormal morphology and synaptogenic signaling in astrocytes following prenatal opioid exposure

Niebergall,

Weekley,

Mazur

et al. 2024

Preprint

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In recent decades, there has been a dramatic rise in the rates of children being born afterin uteroexposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a strong influence on synaptic development, secreting factors that both promote and inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist, buprenorphine, on astrocyte synaptogenic signaling and morphological development in cortical cell culture. Acute buprenorphine treatment had no effect on excitatory synapse number in astrocyte-free neuron cultures. In conditions where neurons shared culture media with astrocytes, buprenorphine attenuated the synaptogenic capabilities of astrocyte-secreted factors. Neurons cultured from drug-naïve mice showed no change in synapses when treated with factors secreted by astrocytes from POE mice. However, this same treatment was synaptogenic when applied to neurons from POE mice, suggestive of a complex neuroadaptive response that maintains synaptogenic pathways in the face of impaired astrocyte signaling. In addition to promoting morphological and connectivity changes in neurons, POE exerted a strong influence on astrocyte development, disrupting their structural maturation and promoting the accumulation of lipid droplets (LD), suggestive of a maladaptive stress response in the developing nervous system.

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“…As noted above, ethanol consumption has sex-specific effects on gene expression in astrocytes ( Wilhelm et al, 2016 ) indicating the potential for environmental factors to effect astrocyte function in sex-specific ways. Recently, astrocyte-derived thrombospondin-1 was reported to induce cortical synaptogenesis in a sex-specific manner ( Mazur et al, 2021 ). Taken together, sex differences in astrocyte regulation of behavior are likely but remain unexplored.…”

Section: Challenges and Future Prospectsmentioning

confidence: 99%

From Synapses to Circuits, Astrocytes Regulate Behavior

Lyon

Allen

2022

Front. Neural Circuits

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Astrocytes are non-neuronal cells that regulate synapses, neuronal circuits, and behavior. Astrocytes ensheath neuronal synapses to form the tripartite synapse where astrocytes influence synapse formation, function, and plasticity. Beyond the synapse, recent research has revealed that astrocyte influences on the nervous system extend to the modulation of neuronal circuitry and behavior. Here we review recent findings on the active role of astrocytes in behavioral modulation with a focus on in vivo studies, primarily in mice. Using tools to acutely manipulate astrocytes, such as optogenetics or chemogenetics, studies reviewed here have demonstrated a causal role for astrocytes in sleep, memory, sensorimotor behaviors, feeding, fear, anxiety, and cognitive processes like attention and behavioral flexibility. Current tools and future directions for astrocyte-specific manipulation, including methods for probing astrocyte heterogeneity, are discussed. Understanding the contribution of astrocytes to neuronal circuit activity and organismal behavior will be critical toward understanding how nervous system function gives rise to behavior.

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Astrocyte-Derived Thrombospondin Induces Cortical Synaptogenesis in a Sex-Specific Manner

Abstract: Astrocyte-derived thrombospondin induces cortical synaptogenesis in a sex-specific manner.

Cited by 18 publications

References 55 publications

Human hippocampal astrocytes: Computational dissection of their transcriptome, sexual differences and exosomes across ageing and mild‐cognitive impairment

Human hippocampal astrocytes: Computational dissection of their transcriptome, sexual differences and exosomes across ageing and mild‐cognitive impairment

Abnormal morphology and synaptogenic signaling in astrocytes following prenatal opioid exposure

From Synapses to Circuits, Astrocytes Regulate Behavior

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