PV interneurons evoke astrocytic Ca2+ responses in awake mice, which contributes to neurovascular coupling.

Neurovascular coupling (NVC) modulates cerebral blood flow to match increased metabolic demand during neuronal excitation. Activation of inhibitory interneurons also increase blood flow, but the basis for NVC caused by interneurons is unclear. While astrocyte Ca2+ levels rise with excitatory neural transmission, much less is known with regards to astrocytic sensitivity to inhibitory neurotransmission. We performed two-photon microscopy in awake mice to examine the correlation between astrocytic Ca2+ and NVC, evoked by activation of either all (VGATIN ) or only parvalbumin-positive GABAergic interneurons (PVIN ). Optogenetic stimulation of VGATIN and PVIN in the somatosensory cortex triggered astrocytic Ca2+ increases that were abolished by anesthesia. In awake mice, PVIN evoked astrocytic Ca2+ responses with a short latency that preceded NVC, whereas VGATIN evoked Ca2+ increases that were delayed relative to the NVC response. The early onset of PVIN evoked astrocytic Ca2+ increases depended on noradrenaline release from locus coeruleus as did the subsequent NVC response. Though the relationship between interneuron activity and astrocytic Ca2+ responses is complex, we suggest that the rapid astrocyte Ca2+ responses to increased PVIN activity shaped the NVC. Our results underline that interneuron and astrocyte-dependent mechanisms should be studied in awake mice.

Extracellular Vesicles in Skin Wound Healing.

Each year, millions of individuals suffer from a non-healing wound, abnormal scarring, or injuries accompanied by an infection. For these cases, scientists are searching for new therapeutic interventions, from which one of the most promising is the use of extracellular vesicles (EVs). Naturally, EV-based signaling takes part in all four wound healing phases: hemostasis, inflammation, proliferation, and remodeling. Such an extensive involvement of EVs suggests exploiting their action to modulate the impaired healing phase. Furthermore, next to their natural wound healing capacity, EVs can be engineered for better defined pharmaceutical purposes, such as carrying specific cargo or targeting specific destinations by labelling them with certain surface proteins. This review aims to promote scientific awareness in basic and translational research of EVs by summarizing the current knowledge about their natural role in each stage of skin repair and the most recent findings in application areas, such as wound healing, skin regeneration, and treatment of dermal diseases, including the stem cell-derived, plant-derived, and engineered EVs.

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice.

The pathogenesis of Alzheimer's disease (AD), a slowly-developing age-related neurodegenerative disorder, is a result of the action of multiple factors including deregulation of Ca2+ homeostasis, mitochondrial dysfunction, and dysproteostasis. Interaction of these factors in astrocytes, principal homeostatic cells in the central nervous system, is still poorly understood. Here we report that in immortalized hippocampal astrocytes from 3xTg-AD mice (3Tg-iAstro cells) bioenergetics is impaired, including reduced glycolysis and mitochondrial oxygen consumption, and increased production of reactive oxygen species. Shotgun proteomics analysis of mitochondria-ER-enriched fraction showed no alterations in the expression of mitochondrial and OxPhos proteins, while those related to the ER functions and protein synthesis were deregulated. Using ER- and mitochondria-targeted aequorin-based Ca2+ probe we show that, in 3Tg-iAstro cells, ER was overloaded with Ca2+ while Ca2+ uptake by mitochondria upon ATP stimulation was reduced. This was accompanied by the increase in short distance (≈8-10 nm) contact area between mitochondria and ER, upregulation of ER-stress/unfolded protein response genes Atf4, Atf6 and Herp, and reduction of global protein synthesis rate. We suggest that familial AD mutations in 3Tg-iAstro cells induce mitochondria-ER interaction changes that deregulate astrocytic bioenergetics, Ca2+ homeostasis and proteostasis. These factors may interact, creating a pathogenic loop compromising homeostatic and defensive functions of astroglial cells predisposing neurons to dysfunction.