Cellular/Molecular
Unfolding the Stargazin Story
Wim Vandenberghe, Roger A. Nicoll, and David S. Bredt
(see pages 1095-1102)
The observation a few years ago that stargazer mice have only a few functional AMPA receptors in cerebellar granule cells led to the suggestion that the underlying protein, stargazin, was involved in receptor trafficking. In the mutant mice, AMPA receptors are not detected on the granule cell surface. In principle, such an effect could arise from impaired trafficking or enhanced endocytosis. However, biochemical studies suggest that stargazin is important for export of AMPA receptors from the endoplasmic reticulum (ER) to the Golgi. This week, Vandenberghe et al. provide further support for this mechanism and exclude a role for constitutive endocytosis. Glutamate receptor 1 (GluR1) reached the surface of COS cells only when cotransfected with stargazin. Interestingly, the authors found a telltale sign of abnormal ER processing, the so-called unfolded protein response (UPR), in stargazin-deficient cells. Proteasome inhibitors strongly induced the UPR and rescued surface expression of GluR1, suggesting stargazin chaperones GluR1 through early steps in its folding or assembly.
Development/Plasticity/Repair
Antidepressants, BDNF, and the Dentate Gyrus
Mikko Sairanen, Guilherme Lucas, Patrik Ernfors, Maija Castrén, and Eero Castrén
(see pages 1089-1094)
Why does it take weeks for the clinical effects of antidepressants to develop? It has not escaped notice that this time course is similar to the antidepressant-induced enhancement of neurogenesis in the dentate gyrus and upregulation of brain-derived neurotrophic factor (BDNF) and its receptor trkB. In this week's Journal, Sairanen et al. assess BDNF- and trkB-mediated signaling in mice chronically injected with antidepressants. They compared wild-type mice with transgenic mice that had impaired BDNF signaling, either one BDNF allele (+/-) or a truncated trkB receptor. After antidepressant treatment, the authors used bromode-oxyuridine to label newborn neurons. At 24 h, all of the mice had similar numbers of labeled neurons, but 3 weeks later, newborn neurons were reduced in the transgenic mice. Antidepressants increased apoptotic markers, suggesting that drug treatment may affect turnover rate rather than just proliferation. The reduced long-term survival of newborn neurons in BDNF-deficient mice indicates that survival depends on BDNF signaling.
Behavioral/Systems/Cognitive
Molluscan Memory Gas
Sergei A. Korneev, Volko Straub, Ildikó Kemenes, Elena I. Korneeva, Swidbert R. Ott, Paul R. Benjamin, and Michael O'Shea
(see pages 1188-1192)
The gaseous neurotransmitter nitric oxide (NO) has been associated with synaptic plasticity in both vertebrates and invertebrates. In the mollusc Lymnaea stagnalis, NO is necessary for chemosensory activation of feeding and associative conditioning of feeding [a form of long-term memory (LTM)]. NO is produced by NO synthases (NOSs), of which there are two in Lymnaea. This week, Korneev et al. report that Lym-neuronal NOS1 (nNOS1) expression increased within 6 h after an associative conditioning trial, boosting NO production at a critical period for LTM. The increase was specific to the cerebral giant cell (CGC), a modulatory neuron that is essential to the LTM network. In addition to the nNOS isoforms, the authors also examined an anti-NOS pseudogene, a noncoding, antisense RNA that binds NOS mRNA and prevents its expression. Two hours before nNOS1 upregulation, CGC expression of anti-NOS expression fell. Thus the regulation of these related genes in a single neuron is a key component in molluscan LTM.
Diagram showing the three-pronged approach for treatment after removal of the eighth thoracic segment of the rat spinal cord. Grafts with OEG were placed on either side of a Schwann cell/Matrigel bridge. A pump infused chondroitinase (cABC). See the article by Fouad et al. for details.
Neurobiology of Disease
Crossing Bridges to Spinal Cord Regeneration
Karim Fouad, Lisa Schnell, Mary B. Bunge, Martin E. Schwab, Thomas Liebscher, and Damien D. Pearse
(see pages 1169-1178)
Unfortunately, there seem to be plenty of obstacles to neuron regeneration after spinal cord injury. This week, Fouad et al. adopt a multifaceted approach to optimize regeneration in adult rats after spinal cord transection. They tried a combination of steps, none of which has proved overwhelmingly successful alone. First, they inserted the rostral and caudal stumps of the transected spinal cord into a guidance channel seeded with Schwann cells to provide a supportive substrate. In addition, they grafted olfactory ensheathing glia (OEG) at sites rostral and caudal to the injury. Finally, in some rats, they treated the glial scar with chondroitinase ABC (cABC) to degrade inhibitory chondroitin sulfate proteoglycans. The combination resulted in significant functional recovery, increased myelinated axons in the bridge, and serotonergic fibers that extended beyond the bridge to the caudal spinal cord. Although descending motor pathways such as the corticospinal tract did not make it through the bridge, the strategy offers promise.
