Low intensity rTMS has sex-dependent effects on the local response of glia following a penetrating cortical stab injury

• Published in: Experimental neurology Vol. 295; pp. 233 - 242
• Main Authors: Clarke, Darren, Penrose, Marissa A., Harvey, Alan R., Rodger, Jennifer, Bates, Kristyn A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2017
• Subjects: Aging; Animals; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Central nervous system injury; Cerebral Cortex - injuries; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Female; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Image Processing, Computer-Assisted; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Microglia; Neuroglia - metabolism; Neuroglia - pathology; Proteoglycans; Repetitive transcranial magnetic stimulation; Sex Characteristics; Sex differences; Transcranial Magnetic Stimulation - methods; Wounds, Stab - metabolism; Wounds, Stab - pathology; Wounds, Stab - therapy; Proteoglycans; Astrocytes; Aging; Sex differences; Repetitive transcranial magnetic stimulation; Central nervous system injury; Microglia
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2017.06.019

Repetitive transcranial magnetic stimulation (rTMS), a non-invasive form of brain stimulation, has shown experimental and clinical efficacy in a range of neuromodulatory models, even when delivered at low intensity (i.e. subthreshold for action potential generation). After central nervous system (CNS) injury, studies suggest that reactive astrocytes and microglia can have detrimental but also beneficial effects; thus modulating glial activity, for example through application of rTMS, could potentially be a useful therapeutic tool following neurotrauma. Immunohistochemistry was used to measure the effect of low intensity rTMS (LI-rTMS) on GFAP (astrocyte), IBA1 (microglial), and CS56 (proteoglycan) expression in a unilateral penetrating cortical stab injury model of glial scarring in young adult and aged male and female C57BL6/J mice. Mice received contralateral low frequency, ipsilateral low frequency, ipsilateral high frequency or sham LI-rTMS (4–5mT intensity), for two weeks following injury. There was no significant difference in the overall volume of tissue containing GFAP positive (+) astrocytes, IBA1+ microglia, or proteoglycan expression, between sham and LI-rTMS-treated mice of all ages and sex. Importantly however, the density of GFAP+ astrocytes and IBA1+ microglia immediately adjacent to the injury was significantly reduced following ipsilateral low and high frequency stimulation in adult and aged females (p≤0.05), but was significantly increased in adult and aged males (p≤0.05). LI-rTMS effects were generally of greater magnitude in aged mice compared to young adult mice. These results suggest that sex differences need to be factored into therapeutic rTMS protocols. In particular, more work analyzing frequency and intensity specific effects, especially in relation to age and sex, is required to determine how rTMS can best be used to modify glial reactivity and phenotype following neurotrauma. •Low intensity rTMS reduced the density of GFAP+ cells and IBA1+ cells around the injury site in adult and aged female mice.•Low intensity rTMS increased the density of GFAP+ cells and IBA1+ cells around the injury site in adult and aged male mice.•Low intensity rTMS did not affect the volume of the glial scar or chondroitin sulfate expression.