Editors' ChoiceNeuroscience

Signals from glia to neurons

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Science Signaling  15 Dec 2015:
Vol. 8, Issue 407, pp. ec369
DOI: 10.1126/scisignal.aae0571

Glial cells actively participate in the maintenance of neuronal circuits. Two papers describe specific functions of two distinct populations of glial cells in the adult mammalian brain: NG2 cells in the prefrontal cortex and astrocytes in the neurogenic niche of the hippocampus. NG2 cells are highly proliferative glial cells and the precursors of the myelinating oligodendrocytes, but their distribution in the brain is broad and not limited to areas containing myelination. Birey et al. generated mice inducibly and reversibly lacking NG2 glia throughout the brain or specifically in the prefrontal cortex (loss of NG2 glia was not 100%, enabling these highly proliferative cells to recover after withdrawal of the inducing agent). These mice exhibited reduced activity of pyramidal neurons and, in the brain, reduced abundance of the GluR1 subunit of glutamate receptors at the plasma membrane and reduced phosphorylation of GluR1, consistent with a reduction in glutamatergic signaling. Loss of NG2 glia also reduced the abundance of astrocytic glutamate transporters and impaired glutamate uptake. These phenotypes resemble those associated with major depressive disorder (MDD), and the NG2-deficient mice exhibited “depressive-like” behaviors in various tests. Reduced NG2 glial density also occurred in mice exposed to chronic social stress, and a similar reduction in NG2 glial cells was detected in the prefrontal cortex of postmortem brain tissue from patients with MDD. Conditioned medium from cultured primary mouse NG2 cells increased the amount of glutamate transporters at the plasma membrane of cultured astrocytes and enhanced GluR1 phosphorylation in primary neuron cultures. Transcriptional analysis indicated that a reduction in fibroblast growth factor 2 (FGF2) may mediate the effects of NG2 loss, and knocking down FGF2 in the prefrontal cortex resulted in mice that displayed depressive-like behaviors. Thus, this study indicated that NG2 glial cells provide FGF2 to support glutamatergic signaling and that loss of this signal leads to changes in neuronal activity that contribute to depression.

Sultan et al. also used inducible mouse models to explore the role of vesicular release from astrocytes on glutamatergic synapses formed in the hippocampus by neurons produced in the adult mouse brain (adult-born neurons). The mice exhibited mosaic induction of compromised astrocyte vesicular release, creating an in-animal control. In regions where the adult-born neuron crossed the release-compromised astrocytes, dendritic protrusion density and protrusion head diameter were reduced compared with regions of the same neuron that crossed areas of normal astrocytes or dendrites in adult-born neurons in control littermates. These data indicated that astrocytes released local signals that facilitate spine maturation of adult-born neurons. Furthermore, despite having similar numbers of newly born neurons (labeled with BrdU) a month later, the mice deficient in astrocytic vesicular release had reduced numbers of the labeled neurons, consistent with the importance of synaptic activity for neuronal survival. Consistent with compromised synaptic activity, electrophysiological analysis showed reduced evoked and spontaneous activity of the adult-born neurons in the mice with vesicle release–compromised astrocytes. Adult-born neurons transition from an initially “silent” state to an active one through GABA-mediated conversion of glutamate synapses with only NMDA-type glutamate receptors to synapses with AMPA-type glutamate receptors. Analysis of the concentrations of various ligands or coligands for these receptors in the brains of the vesicle release–compromised mice showed that the coligand for NDMA receptors, D-serine, was reduced. Indeed, administration of D-serine to the vesicle release–compromised mice restored dendritic morphology to that of control animals, suggesting that D-serine is the key signal released by astrocytes that locally stabilizes glutamatergic synapses from adult-born neurons. Together, these two studies identify molecular signals used by different glial cell populations to regulate glutamatergic circuits.

F. Birey, M. Kloc, M. Chavali, I. Hussein, M. Wilson, D. J. Christoffel, T. Chen, M. A. Frohman, J. K. Robinson, S. J. Russo, A. Maffei, A. Aguirre, Genetic and stress-induced loss of NG2 glia triggers emergence of depressive-like behaviors through reduced secretion of FGF2. Neuron 88, 941–956 (2015). [PubMed]

S. Sultan, L. Li, J. Moss, F. Petrelli, F. Cassé, E. Gebara, J. Lopatar, F. W. Pfrieger, P. Bezzi, J. Bischofberger, N. Toni, Synaptic integration of adult-born hippocampal neurons is locally controlled by astrocytes. Neuron 88, 957–972 (2015). [PubMed]