title: 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.NEW & NOTEWORTHYWe 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.
authors.affiliation: Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan.|Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan.
authors.forename: Joseph W
authors.identifier: 0000-0001-5110-0819
authors.initials: JW
authors.lastname: Salatino
authors.affiliation: Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan.|Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan.|Department of Electrical and Computer Engineering, Michigan State University, East Lansing, Michigan.
authors.forename: Bailey M
authors.initials: BM
authors.lastname: Winter
authors.affiliation: Department of Computer Science and Engineering, Michigan State University, East Lansing, Michigan; and.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Drazin
authors.affiliation: Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan; epurcell@egr.msu.edu.|Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan.|Department of Electrical and Computer Engineering, Michigan State University, East Lansing, Michigan.|Neuroscience Program, Michigan State University, East Lansing, Michigan.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Purcell
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D005260:Female; D009044:Motor Cortex / Q000166:cytology / Q000601:surgery*; D058117:Neural Prostheses / Q000009:adverse effects*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019919:Prosthesis Implantation / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C493466:Slc17a7 protein, rat; C118623:Slc32a1 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins
keywords: neuroprostheses; reactive glia; synaptic markers