Astrocyte heterogeneity across the brain and spinal cord occurs developmentally, in adulthood and in response to demyelination

Abstract

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.

Large felid leucoencephalomyelopathy in a Sumatran tiger (Panthera tigris sumatrae) from an Australian zoo

“…GFAP is the principal intermediate filament protein in astrocytes and is involved in astrocytic functions as diverse as regulation, synaptic plasticity and reactive gliosis. Moreover, different subpopulations of astrocytes have distinct GFAP isoforms that subserve different subtype‐specific functions . Induction of GFAP expression is the main indicator of astroglial activation and the astrocytic reaction to neural injury is characterised by hypertrophy and increased GFAP expression …”

“…The markers were: glial fibrillary acidic protein (GFAP), aldehyde dehydrogenase 1 family member L1 (ALDH1L1) and alpha‐B‐crystallin (CRYAB). The phenotype of astrocytes is largely defined by the cytoplasmic intermediate filament protein, GFAP, and although not all astrocytes express light microscopically detectable GFAP immunohistochemically, its expression is particularly robust in reactive astrocytes . ALDH1L1 is a recently discovered pan‐astrocytic cytoplasmic marker that is more homogeneously expressed throughout the brain than the classical astrocytic marker, GFAP; it labels both GFAP‐positive and GFAP‐negative astrocytes .…”

Glial fibrillary acidic protein expression alters astrocytic chemokine release and protects mice from cuprizone‐induced demyelination

“…The aim of our study was to clarify the role of enhanced GFAP expression in astrocytes during demyelinating diseases. GFAP expression is strictly regulated and known to be higher in the developing and demyelinating adult spinal cord in comparison to the brain, which indicates regional heterogeneity (Yoon, Walters, Paulsen, & Scarisbrick, ). Different GFAP expression levels in astrocytes seem to influence developmental specialization and response in the context of injury and disease.…”

Kallikrein-related peptidase 6 orchestrates astrocyte form and function through proteinase activated receptor-dependent mechanisms

“…While the PAR gated signaling cascade(s) mediating Klk6-PAR-stellation remain to be fully elucidated, it is likely that protein kinase C (PKC) plays a prominent role, since the PKC inhibitor Go6983 blocks Klk6-astrocyte stellation (Scarisbrick et al 2012a). We note that each of these studies examined astrocytes derived from cortices of the postnatal mouse brain and any differences across brain regions (Farmer et al 2017; Yoon et al 2017), or in aged astrocytes, will be an important line of future investigation.…”

“…We therefore propose that Klk6 and/or the receptors it activates are ideally positioned as targets to modify astroglial physiology and the impact of astroglial dynamics on neural function in the intact, injured and regenerating CNS. In such a model we will need to consider that the nature of astrogliosis varies regionally in the CNS and with the type and state of the injury (Anderson et al 2014; Morel et al 2017; Yoon et al 2017). Also, different inflammatory mediators generate markedly different GPCR and G protein expression and astrocyte calcium signaling transients (Hamby et al 2012), including PAR expression (Noorbakhsh et al 2005; Radulovic et al 2015; Radulovic et al 2016).…”