Microglial Nogo delays recovery following traumatic brain injury in mice

Author:

Glotfelty Elliot J.12ORCID,Hsueh Shih‐Chang1ORCID,Claybourne Quia3ORCID,Bedolla Alicia4ORCID,Kopp Katherine O.1ORCID,Wallace Tonya5ORCID,Zheng Binhai6ORCID,Luo Yu4ORCID,Karlsson Tobias E.2ORCID,McDevitt Ross A.3ORCID,Olson Lars2,Greig Nigel H.1ORCID

Affiliation:

1. Drug Design & Development Section, Translational Gerontology Branch Intramural Research Program National Institute on Aging, NIH Baltimore Maryland USA

2. Department of Neuroscience Karolinska Institutet Stockholm Sweden

3. Comparative Medicine Section, National Institute on Aging NIH Baltimore Maryland USA

4. Department of Molecular Genetics and Biochemistry, College of Medicine University of Cincinnati Cincinnati Ohio USA

5. Flow Cytometry Unit National Institute on Aging Baltimore Maryland USA

6. Department of Neurosciences, School of Medicine University of California San Diego La Jolla California USA

Abstract

AbstractNogo‐A, B, and C are well described members of the reticulon family of proteins, most well known for their negative regulatory effects on central nervous system (CNS) neurite outgrowth and repair following injury. Recent research indicates a relationship between Nogo‐proteins and inflammation. Microglia, the brain's immune cells and inflammation‐competent compartment, express Nogo protein, although specific roles of the Nogo in these cells is understudied. To examine inflammation‐related effects of Nogo, we generated a microglial‐specific inducible Nogo KO (MinoKO) mouse and challenged the mouse with a controlled cortical impact (CCI) traumatic brain injury (TBI). Histological analysis shows no difference in brain lesion sizes between MinoKO‐CCI and Control‐CCI mice, although MinoKO‐CCI mice do not exhibit the levels of ipsilateral lateral ventricle enlargement as injury matched controls. Microglial Nogo‐KO results in decreased lateral ventricle enlargement, microglial and astrocyte immunoreactivity, and increased microglial morphological complexity compared to injury matched controls, suggesting decreased tissue inflammation. Behaviorally, healthy MinoKO mice do not differ from control mice, but automated tracking of movement around the home cage and stereotypic behavior, such as grooming and eating (termed cage “activation”), following CCI is significantly elevated. Asymmetrical motor function, a deficit typical of unilaterally brain lesioned rodents, was not detected in CCI injured MinoKO mice, while the phenomenon was present in CCI injured controls 1‐week post‐injury. Overall, our studies show microglial Nogo as a negative regulator of recovery following brain injury. To date, this is the first evaluation of the roles microglial specific Nogo in a rodent injury model.

Funder

National Institutes of Health

Vetenskapsrådet

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience,Neurology

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