Date Published: July 10, 2017
Publisher: Public Library of Science
Author(s): Hyesook Yoon, Grant Walters, Alex R. Paulsen, Isobel A. Scarisbrick, Monika Bradl.
Astrocytes have emerged as essential regulators of function and response to injury in the brain and spinal cord, yet very little is known about regional differences that exist. Here we compare the expression of key astroglial markers (glial fibrillary acidic protein (GFAP) and Aldehyde Dehydrogenase-1 Family Member L1 (ALDH1L1)) across these disparate poles of the neuraxis, tracking their expression developmentally and in the context of demyelination. In addition, we document changes in the astrocyte regulatory cytokine interleukin 6 (IL-6), and its signaling partner signal transducer and activator of transcription 3 (STAT3), in vivo and in vitro. Results demonstrate that GFAP expression is higher in the developing and adult spinal cord relative to brain. Comparisons between GFAP and ALDH1L1 expression suggest elevations in spinal cord GFAP during the early postnatal period reflect an accelerated appearance of astrocytes, while elevations in adulthood reflect higher expression by individual astrocytes. Notably, increases in spinal cord compared to whole brain GFAP were paralleled by higher levels of IL-6 and STAT3. Equivalent elevations in GFAP, GFAP/ALDH1L1 ratios, and in IL-6, were observed in primary astrocyte cultures derived from spinal cord compared to cortex. Also, higher levels of GFAP were observed in the spinal cord compared to the brain after focal demyelinating injury. Altogether, these studies point to key differences in astrocyte abundance and the expression of GFAP and IL-6 across the brain and spinal cord that are positioned to influence regional specialization developmentally and responses occurring in the context of injury and disease.
As astrocytes emerge as key regulators of essential physiological functions in the CNS and its response to injury and disease, there is a growing need to more completely understand regional heterogeneity [1, 2]. Given the considerable cytoarchitectural and functional specialization that exists across the CNS, it is not surprising that complementary heterogeneity exists among astrocytes. Astrocyte heterogeneity includes inter- and intra-regional differences that relate to morphology [3, 4], developmental origin , gene expression profiles [6–10], cell-cell interactions , and responses to injury . Distinctions in regional astrocyte properties also extend to the level of receptor and ion channel expression [13–16], transporter expression , gap junction connectivity , and calcium signaling properties [19–21]. Collectively these differences have important implications for not only the physiological properties of astrocytes, but also the contributions they make to CNS function, its development and plasticity, including responses to injury and disease .
The results of the current study demonstrate that astrocytes appear earlier and are more abundant in the developing spinal cord compared to the brain, but show similar abundance in adulthood. However, in adulthood spinal cord astrocytes express higher levels of GFAP compared to those in the brain. The increases in GFAP observed in the spinal cord were paralleled by increases in the GFAP regulatory cytokine, IL-6, and its signaling partner STAT3. Moreover, the levels of GFAP expression per astrocyte were also significantly higher in spinal cord compared to brain in response to focal demyelination. The elevations we observe in GFAP in the spinal cord compared to brain developmentally, in adulthood, and in response to injury highlight not only regional heterogeneity but also the need to better understand the physiological roles of this well studied, but poorly understood protein across the neuraxis.