Cellular/Molecular
SNARE Force Has Multiple Roles in Synaptic Release
Raul E. Guzman, Yvonne N. Schwarz, Jens Rettig, and Dieter Bruns
(see pages 10272–10281)
Action potentials entering a synaptic terminal cause calcium influx, which causes vesicles to fuse with the plasma membrane and release neurotransmitter. Vesicle fusion is facilitated by the SNARE proteins synaptobrevin, present on vesicles, and syntaxin 1 and SNAP-25, on the plasma membrane. These transmembrane proteins associate via SNARE motifs that pull the membranes together. Because previous studies suggested that fusion is the rate-limiting step that determines the timing of EPSCs relative to action potentials, Guzman et al. asked how inserting additional amino acids to increase the distance between the SNARE motif and transmembrane domain of synaptobrevin affects synaptic transmission. Increasing the insertion length reduced the amplitude and delayed the onset of evoked EPSCs, decreased the amplitude and frequency of miniature EPSCs, slowed glutamate accumulation in the synaptic cleft, decreased release probability, and reduced the size of the readily releasable pool of vesicles. Therefore, the ability of SNAREs to bring membranes close together influences many aspects of synaptic function.
Development/Plasticity/Repair
Spike Bursts in Spinal Circuits Influence Pathfinding
Ksenia V. Kastanenka and Lynn T. Landmesser
(see pages 10575–10585)
As axons extend long distances toward their targets, they are guided by many attractive and repulsive environmental cues. While much research has been devoted to identifying these cues and their mechanisms of action, considerably less focus has been given to the role of neural activity in guiding axons. But as motor neurons extend, spinal neural circuits exhibit rhythmic bursting activity, and blocking or slowing this activity with neurotransmitter receptor antagonists causes pathfinding errors. Still, whether these errors result from the change in activity or from disruption of other signaling cascades initiated by neurotransmitters remained uncertain. To answer this question, Kastanenka and Landmesser expressed channelrhodopsin in spinal neurons and then used rhythmic light pulses to restore normal patterns of neural activity while blocking GABA receptors. This eliminated pathfinding errors and restored normal expression of guidance molecule receptors and transcription factors in motor neurons, indicating that the normal activity pattern is required for proper pathfinding.
Behavioral/Systems/Cognitive
Temporal Discounting Rate Helps Determine Movement Speed
Reza Shadmehr, Jean Jacques Orban de Xivry, Minnan Xu-Wilson, and Ting-Yu Shih
(see pages 10507–10516)
Animals usually seek to maximize reward while minimizing effort. In some cases, these desires have opposite effects on the speed of an action: for example, catching prey may require rapid movements, which require more exertion. On the other hand, increasing speed decreases accuracy, so when accuracy is essential, both maximizing reward and minimizing effort drive an animal toward slower action. What then balances these forces to keep actions from becoming infinitely slow? Shadmehr et al. suggest that temporal discounting—the devaluing of distant rewards that underlies the tendency of animals to choose smaller, sooner over larger, later rewards—helps determine the speed of actions. Because slower actions delay reward acquisition, they effectively decrease the value of the reward. Therefore, maximizing subjective value demands rapid action. Computer models that incorporated temporal discounting rates previously measured in monkeys and humans under different conditions, while simultaneously minimizing effort and errors, accurately reproduced variations in saccade speed measured across these groups.
Neurobiology of Disease
FMRP Shapes Expression Pattern of Kv3.1 in Auditory Brainstem
John G. Strumbos, Maile R. Brown, Jack Kronengold, Daniel B. Polley, and Leonard K. Kaczmarek
(see pages 10263–10271)
Fragile X syndrome (FXS) can include mental retardation, autism, attention deficit disorder, and hypersensitivity to auditory stimulation. It results from loss of fragile X mental retardation protein (FMRP), usually via transcriptional silencing. FMRP is an mRNA binding protein that is thought to regulate local translation of many proteins, including some involved in axon growth, neurotransmitter release, postsynaptic structure, and activity-dependent plasticity. Strumbos et al. report that FMRP also binds to mRNA encoding the voltage-gated potassium channel Kv3.1 in synaptic terminals from brainstem. In auditory brainstem nuclei, Kv3.1 is normally expressed in a tonotopic gradient, with highest levels in neurons that respond to high-frequency sound. This gradient was disrupted in mice lacking FMRP. Furthermore, upregulation of Kv3.1 in response to auditory stimulation occurred in wild-type but not knock-out mice. The authors suggest that disrupting the Kv3.1 gradient impairs temporal processing of auditory stimuli, which could contribute to sound hypersensitivity, as well as learning and attention deficits.
Three-dimensional plots of Kv3.1 immunoreactivity in auditory brainstem. In wild-type mice (left) the channels are expressed in a lateromedial gradient. This gradient is disrupted in Fmr1-null mice (right). See the article by Strumbos et al. for details.
