Stochastic nanoroughness modulates neuron–astrocyte interactions and function via mechanosensing cation channels

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-11, Vol.111 (45), p.16124-16129
• Main Authors: Blumenthal, Nils R., Hermanson, Ola, Heimrich, Bernd, Shastri, V. Prasad
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - mortality; Alzheimers disease; amyloid; Animals; Astrocytes; Astrocytes - pathology; Biological Sciences; Brain; Calcium Channels - metabolism; Cell Communication; Cell Differentiation; Cells; Central nervous system; Depolarization; Homeostasis; Humans; Ion channels; Male; Matrix; Mechanotransduction, Cellular; Molecules; Neural stem cells; Neurites; neurodegenerative diseases; Neuroglia; Neurons; Neurons - metabolism; Neurons - pathology; PC12 Cells; Peptides - pharmacology; Physical Sciences; Rats; Spider Venoms - pharmacology; Stem cells; Stochastic models; Survival analysis; Topography
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1412740111

Extracellular soluble signals are known to play a critical role in maintaining neuronal function and homeostasis in the CNS. However, the CNS is also composed of extracellular matrix macromolecules and glia support cells, and the contribution of the physical attributes of these components in maintenance and regulation of neuronal function is not well understood. Because these components possess well-defined topography, we theorize a role for topography in neuronal development and we demonstrate that survival and function of hippocampal neurons and differentiation of telencephalic neural stem cells is modulated by nanoroughness. At roughnesses corresponding to that of healthy astrocytes, hippocampal neurons dissociated and survived independent from astrocytes and showed superior functional traits (increased polarity and calcium flux). Furthermore, telencephalic neural stem cells differentiated into neurons even under exogenous signals that favor astrocytic differentiation. The decoupling of neurons from astrocytes seemed to be triggered by changes to astrocyte apical-surface topography in response to nanoroughness. Blocking signaling through mechanosensing cation channels using GsMTx4 negated the ability of neurons to sense the nanoroughness and promoted decoupling of neurons from astrocytes, thus providing direct evidence for the role of nanotopography in neuron–astrocyte interactions. We extrapolate the role of topography to neurodegenerative conditions and show that regions of amyloid plaque buildup in brain tissue of Alzheimer’s patients are accompanied by detrimental changes in tissue roughness. These findings suggest a role for astrocyte and ECM-induced topographical changes in neuronal pathologies and provide new insights for developing therapeutic targets and engineering of neural biomaterials. Significance The role of soluble signals in neural differentiation and neurodegeneration is well established. However, the impact of nanotopography imposed by macromolecules within brain tissue on neuronal function and pathologies is not fully appreciated. We have discovered that nanoroughness can modulate the function of hippocampal neurons and their relationship with astrocytes. Inhibition of mechanosensing cation channels including Piezo-1, whose distribution is altered by nanotopography, abrogates the effects imposed by nanotopography and the association of neurons with astrocytes. The finding that regions of amyloid plaque buildup in Alzheimer’s involve