Cellular/Molecular
Calcium and Vesicle Recruitment at the Calyx of Held
Nobutake Hosoi, Takeshi Sakaba, and Erwin Neher
(see pages 14286–14298)
When it comes to synaptic vesicles, synapses seem to know a thing or two about supply and demand. High-frequency stimulation increases exocytosis and results in an accelerated recruitment of additional vesicles within the nerve terminal, a process thought to rely on intracellular calcium. This week, Hosoi et al. took advantage of the accessibility of the presynaptic terminal at the calyx of Held to examine the relationship between intracellular calcium and vesicle recruitment. The authors used paired presynaptic and postsynaptic recordings to measure simultaneously presynaptic calcium levels and postsynaptic responses. Replenishment of the fast-releasing vesicle pool increased with presynaptic calcium levels, thus helping to sustain release during high-frequency firing. This relationship was quasilinear, similar to the calcium dependence of facilitation and post-tetanic potentiation. These processes have much slower kinetics than the highly nonlinear calcium dependence of transmitter release and thus appear to be tuned to slowly changing global calcium levels in nerve terminals.
Development/Plasticity/Repair
APP and Neuronal Migration
Tracy L. Young-Pearse, Jilin Bai, Rui Chang, Jessica B. Zheng, Joseph J. LoTurco, and Dennis J. Selkoe
(see pages 14459–14469)
Most of the attention directed at β-amyloid precursor protein (APP) has focused on its cleavage and its cleavage products, such as Aβ, one of the hallmarks of Alzheimer's disease. However, there are clues that full-length APP has important developmental roles. This week, Young-Pearse et al. revisited this issue by knocking down APP using in utero electroporation. In embryonic day 13 (E13) rat embryos, the authors electroporated APP shRNAs along with a fluorescent reporter and then examined cortical development at E19. The APP shRNA prevented migration of labeled cells from the ventricular zone. By E30, the labeled cells remained below the cortical plate as a heterotopia. The trapped cells initially expressed neuronal markers, suggesting that the defect was in migration rather than differentiation. The defect was rescued by full-length APP. In contrast, overexpression of wild-type APP at E13 accelerated migration of labeled cells into the cortical plate.
Knockdown of APP with a short-hairpin RNA caused the abnormal migration of GFP-labeled cells (right). The migration defect was rescued with overexpression of APP695 (left). See the article by Young-Pearse et al. for details.
Behavioral/Systems/Cognitive
Reversing Sleep Deprivation with a Whiff of Orexin-A
Sam A. Deadwyler, Linda Porrino, Jerome M. Siegel, and Robert E. Hampson
(see pages 14239–14247)
This article might appeal to the beleaguered hospital intern or the college student during finals week, both of which must at times combat sleep deprivation. The loss of the hypothalamic neurons that produce orexin-A causes narcolepsy, and the administration of orexin-A produces arousal and increased attention. This week, Deadwyler et al. provide further evidence that orexin-A can counteract the effects of sleep deprivation. Adult rhesus monkeys were sleep deprived for 30–36 h using a combination of videos, music, treats, gentle rattling of their cages, and constant supervision by laboratory personnel. Sounds a lot like a college dorm. The monkeys were then tested on a delayed match-to-sample short-term memory task. Monkeys that received orexin-A, particularly by intranasal spray, showed better performance. The differences were most apparent for trials that were classified as high-load cognitive processes. The superiority of the intranasal delivery may prove useful for potential clinical applications.
Neurobiology of Disease
AD, Omega-3 Fatty Acids, and a Lipoprotein Receptor
Qiu-Lan Ma, Bruce Teter, Oliver J. Ubeda, Takashi Morihara, Dilsher Dhoot, Michael D. Nyby, Michael L. Tuck, Sally A. Frautschy, and Greg M. Cole
(see pages 14299–14307)
This is one of those good-fat–bad-fat stories for your holiday reading. Ma et al. examined the lipid regulation of an ApoE/low-density lipoprotein receptor, the neuronal sortilin-related receptor (SorLA or LR11). LR11 can reduce β-amyloid production by guiding APP in recycling Golgi and early endosome pathways, thus trafficking APP away from β- and γ-secretase. Polymorphisms that reduce LR11 expression also have been associated with increased Alzheimer's disease (AD) risk. The authors report that the essential omega-3 fatty acid docosahexaenoic acid (DHA) increases LR11 in a neuronal cell line and in primary neurons. DHA also increased LR11 in membrane fractions from aged normal mice and in transgenic mice that overexpressed APP. Dietary fish oil had similar effects in rats with increased AD risk. The authors suggest that this regulation may contribute to the reduced AD risk with increased fish consumption.
