Biology subjects

Chandler-Militello, D.

Publications and source records attributed to Chandler-Militello, D..

2 recordsLinked to original sources

bioRxiv2020

Calcium-independent astrocytic lipid release modulates neuronal activity through Kv channels

An accumulating amount of data suggests that Ca2+-dependent gliotransmitter release plays a key role in the modulation of neuronal networks. Here, we tested the hypothesis that in response to agonist exposure, astrocytes release lipid modulators through activation of Ca2+-independent phospholipase A2 (iPLA2) activity. We found that cultured rat astrocytes treated with selective ATP and glutamatergic agonists released arachidonic acid (AA) and/or its derivatives, including the endogenous cannabinoid 2-arachidonoyl-sn-glycerol (2AG) and prostaglandin E2 (PGE2). Surprisingly, the buffering of cytosolic Ca2+ resulted in a sharp increase in agonist-induced lipid release by astrocytes. In addition, the astrocytic release of PGE2 increased miniature excitatory postsynaptic potentials (mEPSPs) by inhibiting the opening of neuronal Kv channels in brain slices. This study provides the first evidence showing that a Ca2+-independent pathway regulates the release of PGE2 from astrocytes and further demonstrates the functional role of astrocytic lipid release in the modulation of synaptic activity. SIGNIFICANCEUntil now, most studies that implicate astrocytes in the modulation of synaptic activity have focused on Ca2+-dependent release of traditional gliotransmitters such as D-serine, ATP, and glutamate. Mobilization of intracellular stores of Ca2+ occurs within a matter of seconds, but this novel Ca2+-independent lipid pathway in astrocytes could occur on a faster time scale and thus play a role in the rapid signaling processes involved in synaptic potentiation, attention, and neurovascular coupling.

neuroscience↗

bioRxiv2019

Human glial progenitor cells effectively remyelinate the demyelinated adult brain

Human glial progenitor cells (hGPCs) can completely myelinate the brains of congenitally hypomyelinated shiverer mice, rescuing the phenotype and extending or normalizing the lifespan of these mice. We asked if implanted hGPCs might be similarly able to broadly disperse and remyelinate the diffusely and/or multicentrically-demyelinated adult CNS. In particular, we asked if fetal hGPCs could effectively remyelinate both congenitally hypomyelinated adult axons, and axons acutely demyelinated in adulthood, using adult shiverer mice and cuprizone-demyelinated mice, respectively. We found that hGPCs broadly infiltrate the adult CNS after callosal injection, and robustly myelinate congenitally-unmyelinated axons in adult shiverer. Moreover, implanted hGPCs similarly remyelinated denuded axons after cuprizone demyelination, whether they were delivered prior to or after initial cuprizone demyelination. Extraction and FACS of hGPCs from cuprizone-demyelinated brains in which they had been resident, followed by RNA-seq of the isolated human hGPCs, revealed their activation of transcriptional programs indicating their initiation of oligodendrocyte differentiation and myelination. These data indicate the ability of transplanted hGPCs to disperse throughout the adult CNS, to myelinate dysmyelinated regions encountered during their parenchymal colonization, and to also be recruited as myelinating oligodendrocytes at later points in life, upon demyelination-associated demand.

neuroscience↗