Gene Expression Analysis of Innate Immune Compromised Mice Reveals Secondary Target Genes in Response to Intracortical Microelectrode Implantation

Clinical applications for intracortical microelectrodes include Brain-Machine Interface for restoration of functions. However, neuroinflammation and subsequent neurodegeneration limit the performance of the microelectrodes. Pathological assessment has been limited to a dozen or so known neuroinflammatory proteins, and only a few groups have begun to explore changes in gene expression following microelectrode implantation. Our initial characterization of gene expression profiles of the neuroinflammatory response to mice implanted with non-functional intracortical probes revealed 22 genes that could inform future therapeutic targets. Emphasis was placed on the largest changes in gene expression, and in genes that are involved in multiple innate immune sets including Cd14, Itgam, and Irak4. Studies to inhibit Cluster of Differentiation 14 (Cd14) improved microelectrode performance for up to two weeks after electrode implantation. However, partial inhibition of the Cd14pathway through either pharmacologic means or the creation of chimera animals resulted in longer-lasting improvements in microelectrode performance. Therefore, the current study investigated the expression of genes in the neuroinflammatory pathway at the tissuemicroelectrode interface in Cd14-/- mice. Our goal was to explore the possibility of a secondary, compensatory mechanism that may require inhibition synergistically with Cd14to enhance microelectrode performance. After microelectrode implantation, 3 genes showed statistically significant differences in expression between the two groups: Aquaporin 4 (Aqp4), C-X-C Motif Chemokine Ligand 10 (CXCL10), and Interleukin 2 Receptor Subunit Gamma (IL2RG). The decreased expression of Aqp4 at 6 hours and 24 hours post-implantation, as well as increased expression of CXCL10 and IL2RG at 2 weeks post-implantation in Cd14-/- mice may help explain why complete Cd14inhibition leads to improved microelectrode performance at acute but not chronic time points, while offering secondary targets for a more comprehensive approach to improving microelectrode performance.