News tips from the Journal of Neuroscience

1. VGLUT2 and the Thalamus
Diederik Moechars, Matthew C. Weston, Sandra Leo, Zsuzsanna Callaerts-Vegh, Ilse Goris, Guy Daneels, A. Buist, M. Cik, P. van der Spek, Stefan Kass, Theo Meert, Rudi D'Hooge, Christian Rosenmund, and R. Mark Hampson

"If in doubt, knock it out" is a familiar strategy in neuroscience these days. As a case in point, this week, Moechars et al. report on mice lacking the vesicular glutamate transporter 2 (VGLUT2). VGLUT2, one of three mammalian transporters responsible for the uptake of glutamate into synaptic vesicles, is abundant in thalamus, midbrain, and brainstem. Homozygous VGLUT2 knock-out animals died at birth because of respiratory failure, and thalamic neurons rescued from these animal almost completely lacked glutamatemediated synaptic transmission as studied in autaptic cultures. Neurons from heterozygous mice, on the other hand, showed reduced amplitude of miniature excitatory postsynaptic responses, indicating that the number of transporters controls vesicular glutamate content. Although heterozygous mice responded normally to a battery of behavior tests including water maze learning, acute nociception, or inflammatory pain, they did not develop neuropathic pain-like behavior. The results suggest a role for VGLUT2- ependent thalamic signaling in neuropathic pain.

2. Putting LIF to Work on Self Renewal
Sylvian Bauer and Paul H. Patterson

The adult brain harbors a supply of neural stem cells that could in principle replace neurons lost to injury or disease. Thus, there has been a considerable search for the right cocktail of factors to unleash the regenerative potential of these neural stem cells. This week, Bauer and Patterson tested the effects of leukemia inhibitory factor (LIF), a cytokine that increases stem cells survival in vitro. Using viral vectors, they overexpressed the gene encoding LIF in the subventricular zone of adult mice, an area that continuously generates new neurons for the olfactory bulb. Surprisingly, exogenous LIF decreased the number of newly generated neurons in the olfactory bulb by keeping neural stem cells in the self-renewing stage rather than spurring them to differentiate into neurons. Because LIF increased the pool of neural stem cells, the authors suggest that adding other factors to this pool might then kick-art the differentiation needed to promote regeneration.

3. CCK and the Nocebo Effect
Fabrizio Benedetti, Martina Amanzio, Sergio Vighetti, and Giovanni Asteggiano

The placebo effect needs no introduction: give patients a "sugar pill" along with a suggestion that it will cure their symptoms, and they feel better. But the opposite occurs if the pill is given with a suggestion that the symptoms will get worse. Benedetti et al. tested this lesser studied phenomenon, the nocebo effect, on physical pain induced by restricting forearm blood flow with a tourniquet during exercise. As expected, giving study volunteers an inert pill that they were told would increase pain, in fact did so. This nocebo effect was coupled with increases in circulating markers of hypothalamic–pituitary– adrenal (HPA) axis activity. Diazepam blocked the increase in both HPA markers and pain sensitivity, whereas proglumide, an antagonist of cholecystokinin receptors, blocked only the pain effects. Thus, it seems that nocebo suggestions induce anticipatory anxiety, leading to hyperactivity of the HPA axis. Anxiety then activates cholecystokinin signaling that increases pain transmission.

4. SCAM Analysis of the ?-Secretase Catalytic Domain
Chihiro Sato, Yuichi Morohashi, Taisuke Tomita, and Takeshi Iwatsubo

Like molecular scissors, proteases chop proteins in pieces. Because they hydrolyze peptide bonds with water, the catalytic domains of these enzymes are usually located within aqueous compartments and thus are "self-lubricating." But some membrane proteases have their active sites buried within the hydrophobic milieu of the cell membrane. So where do they get their water? This week, Sato et al. answer this question for the catalytic core of presenilin 1, an essential component of the ?- secretase complex that cleaves amyloid precursor protein to generate the infamous amyloid-ß peptide. The authors systematically substituted cysteines at every residue in transmembrane domains 6 and 7 of presenilin 1 and then determined their accessibility to a membrane-impermeable reagent that modifies cysteines. From the analysis, they concluded that the two transmembrane domains must form a water-filled, funnel-shaped pore within the enzyme complex where peptide bonds are cleaved.


Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
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