Functional remodeling of subtype-specific markers surrounding implanted neuroprostheses

Abstract

Microelectrode arrays implanted in the brain are increasingly used for the research and treatment of intractable neurological disease. However, local neuronal loss and glial encapsulation are known to interfere with effective integration and communication between implanted devices and brain tissue, where these observations are typically based on assessments of broad neuronal and astroglial markers. However, both neurons and astrocytes comprise heterogeneous cellular populations that can be further divided into subclasses based on unique functional and morphological characteristics. In this study, we investigated whether or not device insertion causes alterations in specific subtypes of these cells. We assessed the expression of both excitatory and inhibitory markers of neurotransmission (vesicular glutamate and GABA transporters, VGLUT1 and VGAT, respectively) surrounding single-shank Michigan-style microelectrode arrays implanted in the motor cortex of adult rats by use of quantitative immunohistochemistry. We found a pronounced shift from significantly elevated VGLUT1 within the initial days following implantation to relatively heightened VGAT by the end of the 4-wk observation period. Unexpectedly, we observed VGAT positivity in a subset of reactive astrocytes during the first week of implantation, indicating heterogeneity in early-responding encapsulating glial cells. We coupled our VGLUT1 data with the evaluation of a second marker of excitatory neurons (CamKiiα); the results closely paralleled each other and underscored a progression from initially heightened to subsequently weakened excitatory tone in the neural tissue proximal to the implanted electrode interface (within 40 μm). Our results provide new evidence for subtype-specific remodeling surrounding brain implants that inform observations of suboptimal integration and performance. We report novel changes in the local expression of excitatory and inhibitory synaptic markers surrounding microelectrode arrays implanted in the motor cortex of rats, where a progressive shift toward increased inhibitory tone was observed over the 4-wk observation period. The result was driven by declining glutamate transporter expression (VGLUT1) in parallel with increasing GABA transporter expression (VGAT) over time, where a reactive VGAT+ astroglial subtype made an unexpected contribution to our findings.

Glial responses to implanted electrodes in the brain

“…BBB breach due to device insertion may be an initiating signal for these events, on the basis of evidence that astrocyte-induced excitatory synaptogenesis follows injury 92 . Furthermore, heightened glutamatergic transmission subsequently activates astrocytic release of transforming growth factor beta 1 (TGF-β1) to induce inhibitory synaptogenesis 93 ; this parallels the observed excitatory-to-inhibitory shift surrounding implanted devices 91 .…”

“…In turn, the resulting plasticity (including synaptogenesis and long-term potentiation or depression 90 ) shapes long-term network function 90,106 , where potentiation favours hyperactivity (seizure activity) and depression results in network silencing. For this, recent evidence suggests immediate, local upregulation of markers of glutamatergic transmission surrounding devices after insertion, suggesting a potential mechanism of heightened synchrony and activity detected by recording electrodes 91 . However, later upregulation of inhibitory neurotransmission (driven by the release of gamma aminobutyric acid (GABA)) suggests a shift towards network silencing and limited signal detection 91 .…”

“…For this, recent evidence suggests immediate, local upregulation of markers of glutamatergic transmission surrounding devices after insertion, suggesting a potential mechanism of heightened synchrony and activity detected by recording electrodes 91 . However, later upregulation of inhibitory neurotransmission (driven by the release of gamma aminobutyric acid (GABA)) suggests a shift towards network silencing and limited signal detection 91 . This shift from elevated glutamatergic to GABAergic tone around implanted electrodes is likely astrocyte induced.…”

“…However, the influence of reactive glia on the synaptic remodelling surrounding implanted devices is only beginning to be explored. In the surroundings of electrode arrays implanted in rat brains, initially heightened excitatory synaptic transporters precede a chronic elevation in markers of inhibitory transmission 91 . BBB breach due to device insertion may be an initiating signal for these events, on the basis of evidence that astrocyte-induced excitatory synaptogenesis follows injury 92 .…”

The role of oligodendrocytes and their progenitors on neural interface technology: A novel perspective on tissue regeneration and repair

“…Likewise, oligodendrocyte cell death can occur indirectly through glutamate signaling via the release of pro-inflammatory cytokines TNF-α and IL-1β from activated microglia [174, 175]. Elevated expression of glutamate transporters has been observed acutely around inserted devices, which may precede NG2 glia and oligodendrocyte excitotoxic cell death, subsequently leading to demyelination and degeneration of axons around chronically implanted microelectrodes and impairing their recording and stimulating potential [176]. …”