Two of the papers, published online in the February 11 Nature Neuroscience, reveal that neurotransmission is alive and kicking in the white matter of the mammalian brain, a region conspicuously devoid of synapses. Axons that run through the white matter terminate in the gray matter, and it is there that synaptic transmission occurs. Maria Kukley and colleagues at the University Clinic Bonn, Germany, and Dwight Bergles and colleagues at Johns Hopkins University School of Medicine, Baltimore, Maryland, report that vesicular glutamate is also released from unmyelinated axons into the white matter itself. Because this release happens in a controlled and quantitative way, it likely has functional significance. Both papers report that white matter glutamate may be crucial for neuron-glia communication.

Working independently, the two groups used similar thinking and experimental design to arrive at this same conclusion. Because glutamate is known to be released from non-synaptic sites, and because glial precursor cells express ionotropic glutamate receptors, both labs looked for electrical currents in glial precursor cells in response to axonal stimulation. Kukley and colleagues used patch clamp recordings of oligodendrocyte precursor cells in corpus callosum slices from young rats (postnatal days 8-16). They found what they call axo-glial currents (AGCs), which are consistent with stimulation of AMPA-type glutamate receptors on the glia. While these AGCs can be spontaneous, they can also be elicited by stimulating neurons that traverse the corpus callosum. Importantly, these currents do not appear to be due to leaky axons, but to a concerted release of glutamate vesicles from the white matter neurons. If leakage were the cause, then repeated stimulation of the neurons should deplete any glutamate vesicles that happen to fuse with the axon membrane, but Kukley and colleagues found that AGC firing was sustained even after they repeatedly stimulated the neurons. In fact, they calculated that the white matter transmission co-opted about eight vesicles per second, which is “well within the known range for neuronal synapses,” they write.

Bergles’s group used a similar strategy. First author Jennifer Ziskin and colleagues focused on glial cells in transgenic mice expressing the DsRed fluorescent protein under the control of the promoter for the proteoglycan NG2, a glial marker. (Kukley and colleagues used NG2 antibodies to identify glial precursors.) They also found that glutamate elicited currents consistent with AMPA receptors, and, to a lesser extent, NMDA receptors. Ziskin and colleagues used mice up to postnatal day 35, and in these animals all DsRed cells tested exhibited AMPAR-mediated currents. “These results indicate that AMPAR signaling is pervasive among the population of NG2+ cells in both the developing and mature corpus callosum,” they write.

Where the two papers diverge slightly is in deciding whether or not the equivalent of a synapse forms between white matter axons and the glia. Kukley and colleagues come down against this, because they found that potential vesicle release sites are not always in the vicinity of NG2-positive membranes. Ziskin and colleagues favor the synaptic idea, because they found ultrastructural trappings of synapses, including apposition of axonal and NG2-positive membranes and the accumulation of small, clear vesicles and mitochondria on axonal membranes juxtaposed to glial. Further experiments may resolve this issue.

The functional significance of this axon-glial communication seems unclear at present. It could be both good and bad. While it could help glial precursors find axons during development, Kukley and colleagues suggest that “…under pathological conditions the widespread release of glutamate along axons might be harmful: axonal transmitter release is likely to contribute to the ability of NMDA receptors to mediate ischemic damage of mature oligodendrocytes.” Bergles and colleagues agree with this assessment, noting that cerebral ischemia causes extensive damage to oligodendrocytes, which can, in turn, lead to loss of myelin. White matter damage is an early feature of AD, as well, but the causes are not clear.

The third paper, published in the February 15 Neuron, also speaks to pros and cons of NMDA receptor signaling. Hilmar Bading and colleagues at Germany’s University of Heidelberg and elsewhere explain why stimulation of NMDA receptors can have both trophic and toxic effects on neurons. Previously it has been suggested that this may simply be a matter of degree—low stimulation promoting survival and high causing toxicity—but Bading and colleagues report that trophic and toxic responses depend on where the receptors are located, not how they are stimulated.

First author Sheng-Jia Zhang and colleagues used whole-genome expression profiling to study receptor signaling. Using cultured mouse hippocampal neurons and a gene chip set that probes more than 20,000 genes, the authors found that activation of synaptic and extrasynaptic NMDA receptors kick-starts two totally different gene expression programs. Synaptic receptor stimulation specifically up- or downregulated 108 and 34 genes, respectively, but only 11 and 1 genes were up- and downregulated by activating extrasynaptic receptors. Synaptic stimulation turned up genes with protective effects, such as the anti-apoptotic Btg2 and Bcl6, whereas extrasynaptic stimulation turned up the pro-cell death gene Clca1, a proposed calcium-activated chloride channel. The two different expression profiles seem consistent with the trophic and toxic effects of NMDA receptors that have been previously described. Though it remains to be seen how the location of NMDA receptors governs signal transduction to the nucleus, the authors note that “...it is unclear which proteins associate specifically with synaptic versus extrasynaptic NMDA receptors.”

One long-term benefit of these new findings is that they could help researchers devise strategies for delivering potential therapeutics to targets where they are needed most. Kukley and colleagues suggest that drugs that modulate transmitter release in white matter might be promising therapeutic targets. Drugs that prevent NMDA-mediated toxicity could have potential for Alzheimer disease, too.—Tom Fagan.

Reference:
Ziskin JL, Nishiyama A, Rubio M, Fukaya M, Bergles DE. Vesicular release of glutamate from unmyelinated axons in white matter. Nature Neuroscience. 2007 Feb 11. Advanced online publication. Abstract

Kukley M, Capetillo-Zarate E, Dietrich D. Vesicular glutamate release from axons in white matter. Nat Neurosci. 2007 Feb 11; [Epub ahead of print] Abstract

Zhang S-J, Steijaert MN, Lau D, Schutz G, Delucinge-Vivier C, Descombes P, Bading H. Decoding NMDA receptor signaling: Identification of genomic programs specifying neuronal survival and death. Neuron. 2007, February 15;53:549–562. Abstract