Development/Plasticity/Repair
Rigid Substrates Inhibit Axon Growth via TRPC1
Patrick C. Kerstein, Bridget T. Jacques-Fricke, Juliana Rengifo, Brian J. Mogen, Justin C. Williams, et al.
(see pages 273–285)
Axons are guided by numerous soluble and substrate-bound cues that promote extension or retraction. The molecular events underlying these effects have been extensively studied, and counterintuitively, both attractive and repulsive cues cause Ca2+ influx into growth cones; opposite effects are achieved by activating different types of Ca2+ channels clustered with different subsets of Ca2+-dependent kinases, phosphatases, and proteases. In addition to guidance molecules, axon growth is influenced by the physical properties of substrates: for example, growth is faster on flexible substrates (like brain tissue) than on more rigid substrates (like muscle). These effects are mediated by mechanosensory channels including TRPC1, as Kerstein et al. show. A partial inhibitor of mechanosensory receptors accelerated growth of Xenopus spinal axons, and removing this inhibitor slowed growth while increasing spontaneous Ca2+ transients and activating the protease calpain in filopodia. Furthermore, growth cones oriented toward a gradient of the inhibitor. These effects occurred only when axons were extending on firm substrates, however, and they were absent in TRPC1-deficient axons.
Activation of TRPC1 (green) by mechanical forces inhibits axon growth in developing Xenopus spinal neurons. Red labels F-actin; blue is β-tubulin. See the article by Kerstein et al. for details.
Systems/Circuits
Electrically Coupled Cells Can Have Distinct Firing Patterns
Kosei Sasaki, Elizabeth C. Cropper, Klaudiusz R. Weiss, and Jian Jing
(see pages 93–105)
Electrical coupling is generally thought to synchronize neurons that have similar functions. Nevertheless, neurons with distinct firing patterns are electrically coupled in some circuits. In the Aplysia buccal (B) ganglion, several neurons that are electrically coupled are active at different times during retraction of the radula (which brings food into the mouth). Sasaki et al. suggest that the firing patterns result from differences in coupling strength, chemical inputs, and intrinsic properties of these cells. B4/5, which is active primarily during the early part of retraction, inhibits all other retraction-phase neurons, preventing them from firing until later in the cycle. Although B64 and B51 were strongly coupled, B64 began firing much earlier, likely because it had a low spike threshold and can generate plateau potentials. B64 also excited B70, which began firing near the end of the normal retraction phase. Finally, although B51 and B71 were strongly coupled and had similar activity patterns, they were morphologically distinct and evoked different activity patterns in B8.
Behavioral/Cognitive
Dopamine D4 Receptor Genotype Influences Longevity
Deborah L. Grady, Panayotis K. Thanos, Maria M. Corrada, Jeffrey C. Barnett Jr., Valentina Ciobanu, et al.
(see pages 286–291)
Health and longevity are influenced by genetic and environmental factors. One's genes can affect longevity not only through direct physiological effects that increase disease risk, but also by influencing behavioral choices such as drug use, thrill seeking, and response to stress. Variation in the number of tandem repeats in a region of the dopamine D4 receptor (DRD4) have been tied to variations in activity levels, stress resilience, and risks of substance abuse and attention deficit hyperactivity disorder. Grady et al. have now found that a population of long-lived people (age 90–109) was more likely than an ethnically matched, younger population to possess a 7-repeat DRD4 allele, suggesting this allele increases longevity. The increased frequency was significant at the genome-wide level only in females, perhaps because early allelic effects are more likely to affect men adversely. The authors attributed the increased longevity to higher-than-normal activity levels in those bearing the 7-repeat allele, and this was supported by evidence from DRD4-deficent mice.
Neurobiology of Disease
Sortilin Mediates Neuronal Uptake of Apolipoprotein and Aβ
Anne-Sophie Carlo, Camilla Gustafsen, Guido Mastrobuoni, Morten S. Nielsen, Tilman Burgert, et al.
(see pages 358–370)
Expression of the transmembrane receptor sortilin is correlated with the severity of neuropathology in Alzheimer's disease (AD). Sortilin triggers apoptosis upon binding immature forms of neurotrophic factors, and levels of these immature proteins are increased in AD, suggesting a likely link between sortilin levels and neurodegeneration. But sortilin may have additional roles in AD. The strongest known risk factor for sporadic AD is possession of the ϵ4 allele of apolipoprotein E (APOE). APOE binds to extracellular cholesterol-rich lipoproteins—which are essential for building and maintaining synapses—and transports them into neurons after binding to transmembrane receptors. APOE is also thought to sequester extracellular β-amyloid (Aβ) peptides and deliver them to cells for degradation. Carlo et al. discovered that besides binding immature neurotrophic factors, sortilin acts as a receptor for APOE. Exogenous expression of sortilin enabled ovary cells to internalize APOE and Aβ. Moreover, knocking out sortilin increased hippocampal levels of APOE and Aβ and accelerated amyloid plaque formation in a mouse model of AD.
