02 May 2003

Neuronal progenitors are faced with many forks on the road to becoming one of more than 1,000 different neurons found in the human central nervous system. Tracking exactly what pathways progenitors take to become a specific type of neuron has proven to be an extremely difficult task, compounded by the multitude of different neurons found in close proximity to each other. However, papers in last week's Neuron and Nature Neuroscience reveal some of the secrets to neuronal maturation, and offer up two new techniques for researchers who study the role of neurogenesis in Alzheimer’s.

Reporting in Neuron, Catherine Dulac and colleagues at Harvard University reveal that olfactory sensory neurons and olfactory progenitor cells differ substantially in their protein complements. First authors Ian Tietjen and Jason Rihel found 197 genes preferentially expressed in the progenitor cells, vs. 187 genes specific to mature olfactory sensory neurons. Progenitor-specific proteins included some members of the Notch signaling pathway, including RBP and Hes6, and proteins that play key roles in cell proliferation, including two members of the Id family, Id1 and Id2, while some of the differentially expressed proteins were found to have no known function.

To arrive at this conclusion, the authors first made cDNA libraries from single cells, a technique Dulac developed to eliminate cross-contamination from other cell types. Tietjen and Rihel then probed these libraries with DNA microarrays that contain thousands of genes. This technique could be adapted to follow maturation of cells in the other major site of adult neurogenesis, the dentate gyrus, which is part of the hippocampus, one of the first areas affected in Alzheimer's. Single-cell libraries could also be used to compare protein expression profiles of normal and diseased neurons from the same individual, as exist, for example, in AD brains. Dulac and colleagues also exploited laser capture microdissection to isolate single cells from tissue slices, a technique that would lend itself well to the studying of individual neurons from diseased tissue.

Similarly, techniques used by Pierre-Marie Lledo of the Pasteur Institute, Paris, France, together with colleagues in the U.S., could be adapted to study neurogenesis in the dentate gyrus. First author Alan Carleton and colleagues used a viral vector to selectively deposit green fluorescent protein (GFP) into newborn cells. Then, they tracked the GFP cells, subjecting them to a battery of electrophysiological tests to monitor their progress into fully fledged neurons. Their data appeared in the advanced online format in Nature Neuroscience.

Five classes of progenitors have previously been described based on cell morphology and how far they have migrated from their birth place-the subventricular zone-into the olfactory bulb. Carleton matched each class with particular electrophysiological properties and the expression of specific proteins. The authors show that class 1 progenitors have no NMDA-type glutamate receptors, for example, while 50 percent of class 2 cells have. In contrast, all classes expressed AMPA-type glutamate receptors and γ-aminobutyric acid (GABA) receptors, suggesting that these are the first neurotransmitter receptors the progenitors make.

Electrophysiologically, classes 1 and 2 appeared immature, as they were unable to generate Na+-mediated action potentials. Classes 3 and 4, however, exhibited spontaneous electrical activity and occasional electrical spikes driven by Na+ currents, while class 5 cells were indistinguishable from surrounding older mature neurons. The latter appear to be integrated into the olfactory bulb neuronal circuitry, as Carleton and colleagues were able to show that these cells fire off spontaneous action potentials and have synaptic contacts with mature neurons.—Tom Fagan

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Papers

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2. Wen PH, Friedrich VL, Shioi J, Robakis NK, Elder GA. Presenilin-1 is expressed in neural progenitor cells in the hippocampus of adult mice. Neurosci Lett. 2002 Jan 25;318(2):53-6. PubMed.
3. Tatebayashi Y, Lee MH, Li L, Iqbal K, Grundke-Iqbal I. The dentate gyrus neurogenesis: a therapeutic target for Alzheimer's disease. Acta Neuropathol. 2003 Mar;105(3):225-32. PubMed.
4. Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem. 2002 Dec;83(6):1509-24. PubMed.