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High frequency electrical stimulation promotes expression of extracellular matrix proteins from human astrocytes.

ABSTRACT: Therapeutic benefits of deep brain stimulation (DBS), a neurosurgical treatment for certain movement disorders and other neurologic conditions, are well documented, but DBS mechanisms remain largely unexplained. DBS is thought to modulate pathological neural activity. However, although astrocytes, the most numerous cell type in the brain, play a significant role in neurotransmission, chemical homeostasis and synaptic plasticity, their role in DBS has not been fully examined. To investigate astrocytic function in DBS, we applied DBS-like high frequency electrical stimulation for 24 h to human astrocytes in vitro and analyzed single cell transcriptome mRNA profile. We found that DBS-like high frequency stimulation negatively impacts astrocyte metabolism and promotes the release of extracellular matrix (matricellular) proteins, including IGFBP3, GREM1, IGFBP5, THBS1, and PAPPA. Our results suggest that astrocytes are involved in the long-term modulation of extra cellular matrix environments and that they may influence persistent cell-to-cell interaction and help maintain neuromodulation over time.

SUBMITTER: Jang JS

PROVIDER: S-EPMC9277158 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMethods for the electrical inhibition of cardiac excitation have long been sought to control excitability and conduction, but to date remain largely impractical. High-amplitude alternating current (AC) stimulation has been known to extend cardiac action potentials (APs), and has been recently exploited to terminate reentrant arrhythmias by producing reversible conduction blocks. Yet, low-amplitude currents at similar frequencies have been shown to entrain cardiac tissues by generation of repetitive APs, leading in some cases to ventricular fibrillation and hemodynamic collapse in vivo. Therefore, an inhibition method that does not lead to entrainment - irrespective of the stimulation amplitude (bound to fluctuate in an in vivo setting) - is highly desirable.Methodology/principal findingsWe investigated the effects of broader amplitude and frequency ranges on the inhibitory effects of extracellular AC stimulation on HL-1 cardiomyocytes cultured on microelectrode arrays, using both sinusoidal and square waveforms. Our results indicate that, at sufficiently high frequencies, cardiac tissue exhibits a binary response to stimulus amplitude with either prolonged APs or no effect, thereby effectively avoiding the risks of entrainment by repetitive firing observed at lower frequencies. We further demonstrate the ability to precisely define reversible local conduction blocks in beating cultures without influencing the propagation activity in non-blocked areas. The conduction blocks were spatiotemporally controlled by electrode geometry and stimuli duration, respectively, and sustainable for long durations (300 s).Conclusion/significanceInhibition of cardiac excitation induced by high-frequency AC stimulation exhibits a binary response to amplitude above a threshold frequency, enabling the generation of reversible conduction blocks without the risks of entrainment. This inhibition method could yield novel approaches for arrhythmia modeling in vitro, as well as safer and more efficacious tools for in vivo cardiac mapping and radio-frequency ablation guidance applications.

Project description:BackgroundThe substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia, delivering inhibitory efferents to the relay nuclei of the thalamus. Pathological hyperactivity of SNr neurons is known to be responsible for some motor disorders e.g. in Parkinson's disease. One way to restore this pathological activity is to electrically stimulate one of the SNr input, the excitatory subthalamic nucleus (STN), which has emerged as an effective treatment for parkinsonian patients. The neuronal network and signal processing of the basal ganglia are well known but, paradoxically, the role of astrocytes in the regulation of SNr activity has never been studied.Principal findingsIn this work, we developed a rat brain slice model to study the influence of spontaneous and induced excitability of afferent nuclei on SNr astrocytes calcium activity. Astrocytes represent the main cellular population in the SNr and display spontaneous calcium activities in basal conditions. Half of this activity is autonomous (i.e. independent of synaptic activity) while the other half is dependent on spontaneous glutamate and GABA release, probably controlled by the pace-maker activity of the pallido-nigral and subthalamo-nigral loops. Modification of the activity of the loops by STN electrical stimulation disrupted this astrocytic calcium excitability through an increase of glutamate and GABA releases. Astrocytic AMPA, mGlu and GABA(A) receptors were involved in this effect.SignificanceAstrocytes are now viewed as active components of neural networks but their role depends on the brain structure concerned. In the SNr, evoked activity prevails and autonomous calcium activity is lower than in the cortex or hippocampus. Our data therefore reflect a specific role of SNr astrocytes in sensing the STN-GPe-SNr loops activity and suggest that SNr astrocytes could potentially feedback on SNr neuronal activity. These findings have major implications given the position of SNr in the basal ganglia network.

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High frequency electrical stimulation promotes expression of extracellular matrix proteins from human astrocytes.

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