Abstract
Morphological alterations in astrocytes are characteristic for post mortem brains of patients affected by major depressive disorder (MDD). Recently, a significant reduction in the coverage of blood vessels (BVs) by aquaporin-4 (AQP-4)-positive astrocyte endfeet has been shown in the prefrontal cortex (PFC) of MDD patients, suggesting that either alterations in the morphology of endfeet or in AQP-4 distribution might be responsible for the disease phenotype or constitute a consequence of its progress. Antidepressant drugs (ADs) regulate the expression of several proteins, including astrocyte-specific ones. Thus, they may target AQP-4 to induce morphological changes in astrocytes and restore their proper shape or relocate AQP-4 to endfeet. Using an animal model of depression, rats selectively bred for high anxiety-like behavior (HAB), we confirmed a reduced coverage of BVs in the adult PFC by AQP-4-immunoreactive (AQP-4-IR) astrocyte processes with respect to non-selected Wistar rats (NAB), thereby validating it for our study. A further evaluation of the morphology of astrocyte in brain slices (ex vivo) and in vitro using an antibody against the astrocyte-specific cytoskeletal protein glial fibrillary acidic protein (GFAP) revealed that HAB astrocytes extended less processes than NAB cells. Furthermore, short-term drug treatment in vitro with the AD fluoxetine (FLX) was sufficient to increase the plasticity of astrocyte processes, enhancing their number in NAB-derived cells and recovering their basal number in HAB-derived cells. This enhanced FLX-dependent plasticity occurred, however, only in the presence of intact AQP-4, as demonstrated by the lack of effect after the downregulation of AQP-4 with RNAi in both NAB and HAB cells. Nonetheless, a similar short-term treatment did neither modulate the coverage of BVs with AQP-4-positive astrocyte endfeet in NAB nor in HAB rats, although dosage and time of treatment were sufficient to fully recover GFAP expression in HAB brains. Thus, we suggest that longer treatment regimes may be needed to properly restore the coverage of BVs or to relocate AQP-4 to astrocyte endfeet. In conclusion, FLX requires AQP-4 to modulate the plasticity of astrocyte processes and this effect might be essential to re-establish a functional glia-vasculature interface necessary for a physiological communication between bloodstream and brain parenchyma.
Highlights
Morphometric examinations of prefrontal cortical (PFC) regions in post mortem brains of patients with major depressive disorder (MDD) revealed alterations in the density of astrocytes, in addition to neurons (Rajkowska et al, 1999; Rajkowska and Stockmeier, 2013)
We evaluated whether the high anxiety-like behavior (HAB) rats as the animal model used for this study, showed a reduced coverage of blood vessels (BVs) by AQP-4-IR endfeet in the prefrontal cortex (PFC), as it was shown in human post mortem brains of MDD patients (Rajkowska et al, 2013)
Using immunohistochemistry to label brain slices with collagen IV, a specific marker of BVs, together with a specific antibody against AQP-4, which is localized to the endfeet of astrocytes surrounding BVs (Papadopoulos and Verkman, 2013), we revealed that in the PFC of HAB rats the BVs showed a 60% reduction in coverage by AQP-4-IR endfeet with respect to NAB rats, similar to the finding in MDD patients [Figure 1; NAB, 0.16 ± 0.04, N = 8; HAB, 0.06 ± 0.02, N = 7; Student’s t-test, t(1,13) = 2.198, ∗p < 0.05]
Summary
Morphometric examinations of prefrontal cortical (PFC) regions in post mortem brains of patients with major depressive disorder (MDD) revealed alterations in the density of astrocytes, in addition to neurons (Rajkowska et al, 1999; Rajkowska and Stockmeier, 2013). Its regulation of water permeability is important for the modulation of astrocyte plasticity, especially for the extension and migration of astrocyte processes during neuronal activity or activity around BVs (Papadopoulos and Verkman, 2013) and to maintain the integrity of the BBB (Zhou et al, 2008). Because of their localization at the BBB, astrocytes may regulate the transport of therapeutic drugs in/out of the brain through their polarized endfeet which interact with BVs (Pardridge, 1999) and mutations in proteins located to the endfeet can predict a positive or negative response to antidepressants (ADs; Uhr et al, 2008). Aqp-4 knockout mice present cognitive deficits similar to those implicated in mood disorders (Skucas et al, 2011) and exhibit an exacerbated depressive-like behavioral response after corticosterone treatment, accompanied by impaired astrocytic functions (Kong et al, 2014)
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