SummaryTwo populations of oligodendrogenic progenitors co-exist within the corpus callosum (CC) of the adult mouse. Local, parenchymal oligodendrocyte progenitor cells (pOPCs) and progenitors generated in the subependymal zone (SEZ) cytogenic niche. pOPCs are committed perinatally and retain their numbers through self-renewing divisions, while SEZ-derived cells are relatively “young,” being constantly born from neural stem cells. We compared the behavior of these populations, labeling SEZ-derived cells using hGFAP:CreErt2 mice, within the homeostatic and regenerating CC of the young-adult and aging brain. We found that SEZ-derived oligodendroglial progenitors have limited self-renewing potential and are therefore not bona fide OPCs but rather “oligodendroblasts” more similar to the neuroblasts of the neurogenic output of the SEZ. In the aged CC their mitotic activity is much reduced, although they still act as a “fast-response element” to focal demyelination. In contrast to pOPCs, they fail to generate mature myelinating oligodendrocytes at all ages studied.

No abstract

The cells that build the nervous system, either this is a small network of ganglia or a complicated primate brain, are called neural stem and progenitor cells. Even though the very primitive and the very recent neural stem cells (NSCs) share common basic characteristics that are hard-wired within their character, such as the expression of transcription factors of the SoxB family, their capacity to give rise to extremely different neural tissues depends significantly on instructions from the microenvironment. In this chapter we explore the nature of the NSC microenvironment, looking through evolution, embryonic development, maturity and even disease. Experimental work undertaken over the last 20 years has revealed exciting insight into the NSC microcosmos. NSCs are very capable in producing their own extracellular matrix and in regulating their behaviour in an autocrine and paracrine manner. Nevertheless, accumulating evidence indicates an important role for the vasculature, especially within the NSC niches of the postnatal brain; while novel results reveal direct links between the metabolic state of the organism and the function of NSCs.

Postnatal brain neural stem and progenitor cells (NSPCs) cluster in anatomically inaccessible stem cell niches, such as the subependymal zone (SEZ). Here, we describe a method for the isolation of NSPCs from live animals, which we term ''milking.'' The intracerebroventricular injection of a release cocktail, containing neuraminidase, integrin-b1-blocking antibody, and fibroblast growth factor 2, induces the controlled flow of NSPCs in the cerebrospinal fluid, where they are collected via liquid biopsies. Isolated cells retain key in vivo selfrenewal properties and their cell-type profile reflects the cell composition of their source area, while the function of the niche is sustained even 8 months post-milking. By changing the target area more caudally, we also isolate oligodendrocyte progenitor cells (OPCs) from the corpus callosum. This novel approach for sampling NSPCs and OPCs paves the way for performing longitudinal studies in experimental animals, for more in vivo relevant cell culture assays, and for future clinical neuro-regenerative applications.

In silico screening of GMQ-like compounds reveals guanabenz1 and sephin1 as new allosteric modulators of acid-sensing ion 2 channel 3 3 4 Abstract 16Acid-sensing ion channels (ASICs) are voltage-independent cation channels that 17 detect decreases in extracellular pH. Dysregulation of ASICs underpins a number 18 of pathologies. Of particular interest is ASIC3, which is recognised as the key 19 sensor of acid-induced pain and is instrumental in the establishment of pain 20 arising from inflammatory conditions, such as rheumatoid arthritis. Thus, the 21 identification of new ASIC3 modulators and the mechanistic understanding of 22 how these compounds modulate ASIC3 could be important for the development 23of new strategies to counteract the detrimental effects of dysregulated ASIC3 24 activity in inflammation. Here, we report the identification of novel ASIC3 25 modulators based on the ASIC3 specific agonist, 2-guanidine-4-26 methylquinazoline (GMQ). Through a GMQ-guided in silico screening of Food 27and Drug administration (FDA)-approved drugs, 5 compounds were selected and 28 tested for their possible modulation of rat ASIC3 (rASIC3) using whole-cell patch-29 clamp electrophysiology. Of the chosen drugs, guanabenz, an α2-adrenoceptor 30 agonist, produced similar effects to GMQ on rASIC3, activating the channel at 31 neutral pH and potentiating its response to mild acidic stimuli. Sephin1, a 32 guanabenz derivative that lacks α2-adrenoceptor activity, has been proposed to 33 act as a selective inhibitor of a regulatory subunit of the stress-induced protein 34 phosphatase 1 (PPP1R15A) with promising therapeutic potential for the 35 treatment of multiple sclerosis. However, we found that like guanabenz, sephin1 36 activates rASIC3 at neutral pH and potentiates its response to acidic stimulation, 37i.e. sephin1 is a novel modulator of rASIC3. Furthermore, docking experiments 38 showed that, like GMQ, guanabenz and sephin1 likely interact with the nonproton 39 ligand-sensing domain of rASIC3. Overall, these data demonstrate the utility of 40 computational analysis for identifying novel ASIC3 modulators, which can be 41 validated with electrophysiological analysis and may lead to the development of 42 better compounds for targeting ASIC3 in the treatment of inflammatory 43 conditions. 44 48 channel (ASIC) family, these voltage-independent, ligand-gated cation channels 49 are activated by extracellular protons [2][3][4] and belong to the amiloride-sensitive 50 epithelial sodium channel/degenerin (ENaC/DEG) ion channel family [5,6]. In 51 mammals, four genes (accn1-4) encode for at least 6 different ASIC subunits 52 (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, ASIC4), which can assemble into 53 homo-and heterotrimeric channels displaying different pH sensitivity, current 54 kinetics and pharmacology [7][8][9]. ASICs are widely expressed in the central and 55 peripheral nervous systems [2,10] and are implicated in a range of physiological 56 and pathological processes including nociception, mechanosensation and 57 learning/me...