This Week in the Journal

Cellular/Molecular

Lurcher Needs Glutamate After All

Rebecca Meier Klein and James R. Howe

Lurcher mice lurch because this natural mutation causes widespread Purkinje cell death. The lurcher phenotype arises from a mutation in the orphan subunit GluRδ2 that is highly expressed in Purkinje cells. The channelopathy was thought to result from constitutive activation of GluRδ2-containing channels, leading to persistent depolarization, calcium entry, and cell death. However, Meier Klein and Howe reexamined this issue using GluR1 channels containing the lurcher mutation. Their results support an alternative explanation. Rather, the increase in channel openings appears to result from the higher affinity of the mutant channels for glutamate and their reduced desensitization. Thus, lurcher channels are activated and remain open, even at nanomolar concentrations of glutamate. Although the authors cannot exclude constitutive (i.e., unliganded) openings, spontaneous openings appear to be dwarfed by glutamate-triggered openings. Based on their kinetic model, the authors suggest that the mutation alters affinity by stabilizing closure of the binding and thus slowing glutamate dissociation.

Development/Plasticity/Repair

Repelling Axons with Sema5A

Jeffrey L. Goldberg, Mauricio E. Vargas, Jack T. Wang, Wim Mandemakers, Stephen F. Oster, David W. Sretavan, and Ben A. Barres

(see pages 4989-4999)

Semaphorins expressed by glial cells during development are among a number of repulsive axon guidance molecules. These cues are critical in development but can also be counterproductive, by reducing regeneration after nerve injury. Now Goldberg et al. take stock of the semaphorins expressed by each subtype of glia in the optic nerve, oligodendrocytes, astrocytes, and glial precursor cells. They find that each uses a unique set. Only oligodendrocytes and their precursors expressed sema5A, which guides axons of retinal ganglion cells (RGCs) into the optic nerve. Notably sema5A was not present in CNS myelin or sciatic nerve. Sema5A in vitro displayed common developmental and postinjury functions. Media containing Sema5A, secreted by transfected human embryonic kidney cells, caused the collapse of RGC growth cones. In addition, DiI-labeled RGC neurons grown on optic or sciatic nerve explants from postnatal day 4 (P4), P8, or adult animals showed axonal growth inhibition. A sema5A antibody blocked this inhibition. Thus sema5A likely contributes to the failure of optic nerve regeneration.

Purified RGCs (red) extend axons with elaborate growth cones (left) that collapse (right) in response to a semaphorin, sema5A, that was found to be expressed by oligodendrocytes and their precursor cells purified from the optic nerve. When purified RGCs were cultured on living optic nerves [nuclei stained with 4′,6′-diamidino-2-phenylindole (DAPI); blue], axon regeneration was improved in the presence of anti-sema5A antibody. See the article by Goldberg et al. for details.

Behavioral/Systems/Cognitive

Where Have I Been Sleeping?

Beata Jarosiewicz and William E. Skaggs

(see pages 5070-5077)

Hippocampal place cells fire when a rat enters a particular part of its environment, an orientation maintenance that does not subside with sleep in rats. During small irregular activity (SIA), a period of heightened arousal during sleep, place cells also fire, presumably to ensure that rats wake ready to respond to their surroundings and not utterly perplexed as to their whereabouts. But do rats take a peek during these brain activity surges, using new visual cues to update the picture, or are the neurons simply recalling what was last seen before dozing off? The latter, suggests a report from Jarosiewicz and Skaggs. They tricked their rodent subjects by slowly rotating the circular platform as the rats slept, thus redistributing the visual cues. Recordings from CA1 neurons revealed that place cells fired in a pattern consistent with the visual positional cues seen before sleep, suggesting memory-dependent maintenance.

Neurobiology of Disease

Examining the Prion Species Barrier

Joaquín Castilla, Alfonso Gutiérrez-Adán, Alejandro Brun, Deirdre Doyle, Belén Pintado, Miguel A. Ramírez, Francisco J. Salguero, Beatriz Parra, Fayna Díaz San Segundo, José M. Sánchez-Vizcaíno, Mark Rogers, and Juan M. Torres

(see pages 5063-5069)

In 2003, bovine spongiform encephalopathy (BSE) was detected in a North American cow, turning the beef industry upside down. Since its major emergence in the United Kingdom in the 1980s, the human form of BSE, variant Creutzfeldt-Jakob disease, has focused attention on the transmissibility of prion diseases. In general, transmission is much more efficient within species, but how high is the barrier for transmission between species? Castilla et al. examined the barrier from cows to pigs using transgenic mice expressing the porcine prion protein gene (poTg). Intracerebral inoculation with a high-titer, but not low-titer, BSE inoculum caused clinical signs of BSE, consistent with a strong species barrier. However, second passage with brain homogenates from low-titer-inoculated mice produced detectable prion protein in new poTg mice. These results suggest that the barrier is not absolute, at least when prion protein is overexpressed at high levels, as in these mice, and that such mice may be useful in monitoring for latent infection.