The ABCs and Ds of Rab3
Oliver M. Schlüter, Frank Schmitz, Reinhard Jahn, Christian Rosenmund, and Thomas C. Südhof
(see pages 6629-6637)
The Rab family of GTP-binding proteins is implicated in a variety of membrane trafficking roles including synaptic vesicle exocytosis. Although mice lacking individual Rab3 proteins have been analyzed, the four isoforms (A-D) make it difficult to assess compensatory effects. Now Schlüter et al. have done the heroic. They made triple and quadruple knock-out mice to examine Rab function. Mice lacking all four isoforms died of respiratory failure soon after birth, although development appeared normal. Of the triple knock-outs, only those expressing Rab3A survived. Thus Rab3 is essential for survival, but the isoforms are redundant, despite their spatially distinct distributions. To examine the effects of Rab3 loss on synaptic vesicle release, the authors cultured hippocampal neurons from the quadruple knock-outs. These neurons had normal spontaneous release, but evoked release was reduced. Thus Rabs are not essential for docking and fusion of synaptic vesicle, but rather modulate the release machinery.
The Dystrophic Growth Cone: Moving But Not Advancing
Veronica J. Tom, Michael P. Steinmetz, Jared H. Miller, Catherine M. Doller, and Jerry Silver
(see pages 6531-6539)
The glial scar that forms in the spinal cord after injury is a major impediment to regeneration of CNS neurons. The result is a tangle of misdirected growth cones stuck in the site of injury. These dystrophic nerve endings were described as “sterile end-bulbs” by Ramón y Cajal, who believed they entered a quiescent state after futile attempts at regeneration. Tom et al. designed a novel in vitro system to mimic the glial scar and assess the motility of such failed growth cones. They recreated a bidirectional gradient of a growth-inhibiting proteoglycan (aggrecan) and a growth-promoting factor (laminin) by drying a drop of the mixture on a glass surface. The dried spot had a higher concentration of aggrecan at the edge. They observed the formation of dystrophic growth cones that were remarkably dynamic, making small movements, as seen with time-lapse microscopy, and showing exaggerated endocytosis. The assay may be useful in screening candidate molecules for promotion of regeneration.
The Pathways of Human Pain
Fred A. Lenz, Shinji Ohara, Rick H. Gracely, Patrick M. Dougherty, and Salil H. Patel
(see pages 6540-6544)
In this week's Journal, Lenz et al. undertake a unique set of experiments in awake humans undergoing thalamic surgery for movement disorders or chronic pain. The authors stimulated nerve tracts at the terminus of the spinothalamic tract (STT), which carries painful stimuli to the brain, and recorded from single thalamic neurons. Interestingly, they uncovered two distinct pain-response pathways. The first was binary, in which painful sensations were either present or absent and had a large projected field on the body. This pathway is likely to act as a general alarm system for harmful stimuli. The second was an analog (graded) system, in which nonpainful sensations (mechanical or thermal, for example) eventually gave way to pain as the stimulus increased. Patients described both types of stimulation with terms usually applied to external stimuli rather than emotional or visceral phenomena. This study adds new information to the ongoing debate about the nature of labeled lines in pain signaling.
Neurobiology of Disease
Revisiting the GPe-STN-GPi Loop in Parkinsonian Monkeys
Jesus Soares, Michele A. Kliem, Ranjita Betarbet, J. Timothy Greenamyre, Bryan Yamamoto, and Thomas Wichmann
(see pages 6417-6426)
Parkinsonism begins with loss of dopamine neurons in the substantia nigra, with a resulting decrease in dopamine in the striatum. The result, goes the conventional wisdom, is decreased activity in the external segment of the globus pallidus (GPe), followed by disinhibition of the subthalamic nucleus (STN) and increased output from the internal pallidal segment (GPi). This view of parkinsonian movements, however, may be too simplistic. Soares et al. now compare 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism with specific GPe lesions in monkeys to reassess the GPe-STN-GPi loop. They made extracellular recordings from neurons in the GPe, STN, and GPi, and observed motor behavior. After MPTP, activity decreased in the GPe and increased in the STN and GPi. However, GPe lesions did not induce parkinsonism. Although decreased activity of the GPe may be necessary for the induction of parkinsonism, it does not appear to be sufficient. The authors suggest that changes in the pattern of firing, and not just the rate, may be important.