Vesicular release of glutamate from unmyelinated axons in white matter

Abstract

Directed fusion of transmitter-laden vesicles enables rapid intercellular signaling in the central nervous system and occurs at synapses within gray matter. Here we show that action potentials also induce the release of glutamate from axons in the corpus callosum, a white matter region responsible for interhemispheric communication. Callosal axons release glutamate by vesicular fusion, which induces quantal AMPA receptor-mediated currents in NG2 + glial progenitors at anatomically distinct axo-glial synaptic junctions. Glutamate release from axons was facilitated by repetitive stimulation and could be inhibited through activation of metabotropic autoreceptors. Although NG2 + cells form associations with nodes of Ranvier in white matter, measurements of conduction velocity indicated that unmyelinated fibers are responsible for glutamatergic signaling with NG2 + glia. This activitydependent secretion of glutamate was prevalent in the developing and mature mouse corpus callosum, indicating that axons within white matter both conduct action potentials and engage in rapid neuronglia communication.The white matter of the CNS contains axons that permit functional interactions among specialized brain regions. The prevailing view is that these axons blindly transmit electrical activity through the white matter to be translated into the release of chemical messengers at synapses in gray matter; this restricted secretion of neurotransmitters at or near terminal active zones helps to maintain the specificity of intercellular communication in the nervous system 1 . Indeed, terminal boutons are rare in white matter, which contains primarily myelinated and unmyelinated axons and a variety of glial cells 2 . Nevertheless, glutamate is released in an activity-dependent manner from white matter 3 , glial cells within these fiber tracts express glutamate receptors 4,5 and glutamate transporters are present to remove glutamate 6 . Furthermore, glutamate-induced excitotoxic damage to oligodendrocytes and their progenitors is often observed after ischemia 7 , which leads to a loss of myelin and is a contributing factor in cerebral palsy. Despite this evidence of glutamatergic signaling in white matter, the mechanisms responsible for glutamate release within these projection pathways have not been determined.Correspondence should be addressed to D.E.B. (dbergles@jhmi.edu).. Note: Supplementary information is available on the Nature Neuroscience website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2007 December 17. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTo define the mechanisms of glutamate release within white matter, we recorded from glial precursor cells that express the proteoglycan NG2 (NG2 + cells) in the corpus callosum; these cells represent a potential target of axon-derived glutamate, as they express ionotropic glutamate receptors 4 , make contact...

Expression of the transcription factor Olig2 in proliferating cells in the adult zebrafish telencephalon

“…OPCs appear to take part in neural network communication. They are connected to neurons via so called axo-glial synaptic junctions (Lin and Bergles, 2002;Ziskin et al, 2007;Hermann et al, 2010). Recent evidence suggests that glutamate can inhibit the division of OPCs via activation of AMPA receptors, thereby regulating the proliferation of these cells (McTigue and Tripathi, 2008).…”

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

“…4a), known to form bona fide synapses with presynaptic neurons and serve as a post-synaptic cell 14–16 . To test the relative contribution of neurons and OPCs to neuroligin-3 secretion, mice expressing cell type-specific, inducible Cre drivers were bred to Nlgn3 fl/fl mice.…”

Electrical signalling properties of oligodendrocyte precursor cells

“…At present it is unclear how these two OPC classes (which are apparently morphologically indistinguishable) relate to the two classes reported by Mallon et al (2002) and Horner et al (2000). The segregation of OPCs into two electrically distinct classes has since been confirmed to exist for OPCs in two separate transgenic mice expressing YFP under the control of the oligodendrocyte-specific Sox10 or PDGFRa promoters (Clarke et al, 2009).Previous electrophysiological studies did not explicitly report the ohmic class of OPC in the white matter (Kukley et al, 2007;Ziskin et al, 2007) or in the grey matter (Bergles et al, 2000;Lin and Bergles, 2004;Jabs et al, 2005; Ge et al, 2006). However, Karram et al (2008) found some grey matter OPCs expressed almost no voltagegated Na þ current (left cell in their fig.…”

“…As a variant of this approach, some antigens can be labelled in living cells, and thus used to select cells for recording, with an antibody binding to an extracellular epitope such as NG2 (Káradóttir et al, 2008). Alternatively, expression of a fluorescent protein like GFP or DsRed, under control of an OPC-specific promoter, can be used to select cells (Belachew et al, 2001; Chittajallu et al, 2004;Ziskin et al, 2007).Both of these methods have the advantage of not relying solely on location in the brain, cell morphology or developmental stage of the animal to define OPCs, but both have problems. Immunocytochemistry after recording requires that the electrode can be removed from the cell without destroying it.…”

“…In the white matter of the corpus callosum the synaptic input to OPCs is from unmyelinated axons (Kukley et al, 2007;Ziskin et al, 2007), suggesting that this synaptic transmission may serve as a signal from active axons to OPCs to instruct them to myelinate the axons. The initial phase of this process may be a suppression of proliferation of OPCs induced by the In the corpus callosum, where almost all the axons are excitatory, Na þ channel expressing OPCs receive excitatory synaptic input from 11 to 140 unmyelinated axons (Kukley et al, 2007;Ziskin et al, 2007). In the cerebellum synaptic input was recorded far more readily in Na þ channel expressing OPCs than in ohmic OPCs (Káradóttir et al, 2008), and could be either an inward glutamatergic current or an outward (under the low [Cl] i conditions used) GABAergic current (Fig.…”