Graphene Oxide Upregulates the Homeostatic Functions of Primary Astrocytes and Modulates Astrocyte-to-Neuron Communication

Abstract

Graphene-based materials are the focus of intense research efforts to devise novel theranostic strategies for targeting the central nervous system. In this work, we have investigated the consequences of long-term exposure of primary rat astrocytes to pristine graphene (GR) and graphene oxide (GO) flakes. We demonstrate that GR/GO interfere with a variety of intracellular processes as a result of their internalization through the endolysosomal pathway. Graphene-exposed astrocytes acquire a more differentiated morphological phenotype associated with extensive cytoskeletal rearrangements. Profound functional alterations are induced by GO internalization, including the upregulation of inward-rectifying K channels and of Na-dependent glutamate uptake, which are linked to the astrocyte capacity to control the extracellular homeostasis. Interestingly, GO-pretreated astrocytes promote the functional maturation of cocultured primary neurons by inducing an increase in intrinsic excitability and in the density of GABAergic synapses. The results indicate that graphene nanomaterials profoundly affect astrocyte physiology in vitro with consequences for neuronal network activity. This work supports the view that GO-based materials could be of great interest to address pathologies of the central nervous system associated with astrocyte dysfunctions.

An Increase in Membrane Cholesterol by Graphene Oxide Disrupts Calcium Homeostasis in Primary Astrocytes

“…Collectively, our current and previously published results support the view that GO is an exploitable material for biomedical applications in neuromedicine, since it is not harmful to neurons and astrocytes and regulates important astrocyte homeostatic functions. However, since GO affects the balance between excitatory and inhibitory signaling in neuronal networks and modulates [Ca 2+ ] i dynamics in primary astrocytes through changes in cholesterol levels, its applicability as functional substrate for prosthetic devices remains to be unequivocally determined.…”

“…poly(ethylene glycol) (PEG)‐SWCNT films had differential effects on astrocytes, with thinner films inducing stellation, and thicker films promoting dedifferentiation with cell enlargement, reduced GFAP expression, and increased proliferation . Graphene oxide (GO) did not affect astrocyte viability in vitro . We have recently shown that GO impacts on astrocyte homeostatic functions by affecting their ability to buffer extracellular K + and glutamate, with repercussions on the excitability of cocultured neurons .…”

The interrupted effect of autophagic flux and lysosomal function induced by graphene oxide in p62-dependent apoptosis of F98 cells

“…In this study, we investigated the cell viability of F98 cells exposed to different concentrations of GO by CCK-8 detection and LDH test, whose result showed the concentration-and time-dependent cytotoxicity. Research reported that GO in a low concentration of 10 µg/mL upregulates the homeostatic functions of primary astrocytes and modulates astrocyte-to-neuron communication without affecting viability [44]. It is expected that GO can cause cell death or increase cell viability depending on the cell line and the dosage [45,46].…”

Cellular Signaling Pathways Activated by Functional Graphene Nanomaterials

“…The intracellular internalization of graphene-based materials triggers a wide variety of cellular responses mediated by the activation of the intracellular signaling network, which affects the cell environmental [ 54 , 55 , 56 ]. The expression of cytokines, growth factors, and gene regulatory proteins emerges from the ability of nanomaterials to modulate a cellular pathway such as apoptosis, cell cycle, inflammation, and metabolic processes [ 57 ].…”