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The impact SARS-CoV-2 has on the neurological system remains unclear, however this preprint offers novel findings on neuronal impacts of SARS-CoV-2. Thus, the main goal of this study is to shed light on how virological features of SARS-CoV-2, specifically the S protein, affects neurological systems. Consequently, the study hypothesizes that the spike protein of SARS-CoV-2 is responsible for neuronal phenotypes without having to be infected by the whole infectious virion. To test this hypothesis, the S1 and S2 subunits of the spike protein were tested separately to assess whether or not they caused any neurological phenotypes measured by micro-electrode arrays. To do so, recombinant SARS-CoV-2 spike protein, S1 subunit, and S2 subunits, and treated neurons from mice were collected. Extracted whole-brain neurons from mice were plated on micro-electrode arrays and then administered purified recombinant spike protein which was then maintained and collected over a two-week period before data was analyzed. While the role of the S protein and its influence on the neuronal system continues to require more investigation, this study offers new insight into the biological and virological properties of SARS-CoV-2 as well as offering new patient care strategies as well as future vaccine design. The study also provides sufficient detail to allow reproduction as well as offer appropriate statistics for analysis and supporting conclusions drawn from the study.

Main findings:

• Purified S1 protein reduces burst activities in neurons.

• Mature neurons were not affected by S1.

• Human anti-S1 antibody rescued the neuronal phenotype caused by S1.

  • Rescue experiment determined whether or not the neuronal phenotype could be reverted.

• Receptor binding domain of of S1 is responsible for reducing reducing burst activity

Major Issues

• Paper claims that its findings can potentially spur the development of future vaccines and research on SARS-CoV-2 and the central nervous system relations. However, the paper does not elaborate on what areas of research need to be specifically achieved to support the paper’s findings.

  • Paper also does not provide a direct link between how its results can influence the development of improved vaccines and existing knowledge about long COVID.

• Manuscript does not discuss limitations to the study or ethical concerns.

Minor Issues

• Data and charts were all located at the end of the paper, so it got confusing having to go back and forth in the paper to find what set of data corresponded with what information in the paper.

Competing interests

The author declares that they have no competing interests.