Effects of immunization with heat-killed Mycobacterium vaccae on autism spectrum disorder-like behavior and epileptogenesis in a rat model of comorbid autism and epilepsy

Zachariah Z Smith; Rebecca A Kubiak; Mathew R Arnold; Kelsey M Loupy; Jeremy A Taylor; Taylor G Crist; Allison E Bernier; Heather M D'Angelo; Jared D Heinze; Christopher A Lowry; Daniel S Barth

doi:10.1016/j.bbi.2020.05.034

Effects of immunization with heat-killed Mycobacterium vaccae on autism spectrum disorder-like behavior and epileptogenesis in a rat model of comorbid autism and epilepsy

Brain Behav Immun. 2020 Aug:88:763-780. doi: 10.1016/j.bbi.2020.05.034. Epub 2020 May 19.

Authors

Affiliations

¹ Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: zachariah.smith@colorado.edu.
² Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: rebecca.kubiak@colorado.edu.
³ Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: arnoldmr@colorado.edu.
⁴ Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: kelsey.loupy@colorado.edu.
⁵ Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: Jeremy.Taylor@colorado.edu.
⁶ Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: tgcrist25@colorado.edu.
⁷ Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: allison.bernier@colorado.edu.
⁸ Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: heather.dangelo@colorado.edu.
⁹ Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: jared.heinze@colorado.edu.
¹⁰ Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO 80309, USA; Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), The Rocky Mountain Regional Medical Center (RMRVAMC), Aurora, CO 80045, USA; Department of Physical Medicine & Rehabilitation and Center for Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO 80045, USA; inVIVO Planetary Health, of the Worldwide Universities Network (WUN), West New York, NJ 07093, USA. Electronic address: christopher.lowry@colorado.edu.
¹¹ Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: daniel.barth@colorado.edu.

PMID: 32442471
DOI: 10.1016/j.bbi.2020.05.034

Abstract

Autism spectrum disorders (ASDs) and epilepsy are often comorbid. The basis for this co-occurrence remains unknown; however, inflammatory stressors during development are a shared risk factor. To explore this association, we tested the effect of repeated immunizations using a heat-killed preparation of the stress-protective immunoregulatory microbe Mycobacterium vaccae NCTC 11,659 (M. vaccae) on the behavioral and epileptogenic consequences of the combined stress-terbutaline (ST) rat model of ASD-like behavior/epilepsy. Repeated immunization of the dam with M. vaccae during pregnancy, followed by immunization of the pups after terbutaline injections, prevented the expression of ASD-like behavior but did not appear to protect against, and may have even enhanced, the spontaneous epileptogenic effects of ST. Maternal M. vaccae injections transferred an anti-inflammatory immunophenotype to offspring, and repeated injections across development prevented ST-induced increases in microglial density at early developmental time points in a region-specific manner. Despite epidemiological comorbidity between ASD/epileptic conditions and shared environmental risk factors, our results suggest that the expression of ASD-like behaviors, but perhaps not epileptogenesis, is sensitive to early anti-inflammatory intervention. These data provide support for the exploration of immunoregulatory strategies to prevent the negative neurodevelopmental behavioral effects of stressors during early critical periods.

Keywords: Autism; Comorbidity; Epilepsy; Mycobacterium vaccae; Neurodevelopment; Seizure; Two-hit.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Autism Spectrum Disorder*
Epilepsy*
Female
Hot Temperature
Immunization
Mycobacteriaceae
Mycobacterium* / immunology
Pregnancy
Rats

Supplementary concepts

Mycolicibacterium vaccae