Abstract
The importance of astrocytes to normal brain functions and neurological diseases has been extensively recognized; however, cellular mechanisms underlying functional and structural plasticities of astrocytes remain poorly understood. Oxytocin (OT) is a neuropeptide that can rapidly change astrocytic plasticity in association with lactation, as indicated in the expression of glial fibrillary acidic protein (GFAP) in the supraoptic nucleus (SON). Here, we used OT-evoked changes in GFAP expression in astrocytes of male rat SON as a model to explore the cellular mechanisms underlying GFAP plasticity. The results showed that OT significantly reduced the expression of GFAP filaments and proteins in SON astrocytes in brain slices. In lysates of the SON, OT receptors (OTRs) were co-immunoprecipitated with GFAP; vasopressin (VP), a neuropeptide structurally similar to OT, did not significantly change GFAP protein level; OT-evoked depolarization of astrocyte membrane potential was sensitive to a selective OTR antagonist (OTRA) but not to tetanus toxin, a blocker of synaptic transmission. The effects of OT on GFAP expression and on astrocyte uptake of Bauer-Peptide, an astrocyte-specific dye, were mimicked by isoproterenol (IPT; β-adrenoceptor agonist), U0126 or PD98059, inhibitors of extracellular signal-regulated protein kinase (ERK) 1/2 kinase and blocked by the OTRA or KT5720, a protein kinase A (PKA) inhibitor. The effect of OT on GFAP expressions and its association with these kinases were simulated by mSIRK, an activator of Gβγ subunits. Finally, suckling increased astrocytic expression of the catalytic subunit of PKA (cPKA) at astrocytic processes while increasing the molecular associations of GFAP with cPKA and phosphorylated ERK (pERK) 1/2. Upon the occurrence of the milk-ejection reflex, spatial co-localization of the cPKA with GFAP filaments further increased, which was accompanied with increased molecular association of GFAP with pERK 1/2 but not with cPKA. Thus, OT-elicited GFAP plasticity is achieved by sequential activation of ERK 1/2 and PKA via OTR signaling pathway in an antagonistic but coordinated manner.
Highlights
Astrocytes are extensively involved in normal brain functions (Vasile et al, 2017) and neurological diseases (Pekny et al, 2016; Verkhratsky et al, 2016)
We linked the roles of phosphorylated ERK (pERK) 1/2 and protein kinase A (PKA) to sucklingevoked glial fibrillary acidic protein (GFAP) plasticity of the supraoptic nucleus (SON) in lactating rats to verify the applicability of identified features of kinase modulation of acute GFAP plasticity
Pretreatment of slices with the OTR antagonist (OTRA) blocked this OT effect (Figure 1Ba). These results summarized in Figures 1Ac,Bb are consistent with the effect of OT on GFAP plasticity in lactating rats (Wang and Hatton, 2009)
Summary
Astrocytes are extensively involved in normal brain functions (Vasile et al, 2017) and neurological diseases (Pekny et al, 2016; Verkhratsky et al, 2016). Increases in phosphorylated extracellular signalregulated protein kinase (pERK) 1/2 elevated GFAP levels (Li D. et al, 2017), an effect similar to that of chronic cAMP/PKA activation (Hsiao et al, 2007). These findings highlight the dependence of GFAP metabolism on interactions between different protein kinases in astrocytes. Determining the interaction between GFAP and these protein kinases in acute physiological processes is important to understand the cellular mechanisms that regulate GFAP/astrocytic plasticity
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