Cellular/Molecular
A Painful TRP Nicole Alessandri-Haber, Olayinka A. Dina, Jenny J. Yeh, Carlos A. Parada, David B. Reichling, and Jon D. Levine (see pages 4444-4452)
TRP (transient receptor potential) channels are involved in a number of sensory transduction pathways. Alessandri-Haber et al. found recently that TRPV4, a polymodal receptor–channel initially described as an osmosensor, contributes to inflammatory pain. They now investigate the role of TRPV4 in a model of neuropathic pain caused by the antimitotic cancer drug Taxol. Taxol, derived originally from the bark of Pacific yew trees, causes a painful sensory neuropathy that limits its maximum therapeutic dose. The authors report that TRPV4 antisense nucleotides injected into rat spinal cord reduced Taxol-induced mechanical hyperalgesia and hypotonic-induced hyperalgesia. Taxol did not alter TRPV4 expression; rather, the hyperalgesia appears to involve TRPV4-associated second messenger cascades. This seems reasonable given the known interaction of Taxol with microtubules and the known cytoskeletal dependence of TRPV4 signaling. The authors' data indicate that integrin/Src tyrosine kinase signaling, which can directly activate TRPV4, underlies Taxol-induced neuropathic pain.
Development/Plasticity/Repair
p75NTR and Growth Cone Dynamics Scott Gehler, Gianluca Gallo, Eric Veien, and Paul C. Letourneau (see pages 4363-4372)
Growth cones navigate toward their targets by first feeling their way along with actin-filled filopodia extending from their leading edge. In this issue, Gehler et al. examine the regulation of filopodial dynamics by neurotrophins. They focused on the p75 neurotrophin receptor (p75NTR) based on previous reports indicating that activated p75NTR increases filopodial formation. The authors found that retinal and dorsal root ganglion neurons from mice lacking the p75NTR were neurotrophin-insensitive, yet grew longer filopodia even than wild-type neurons treated with neurotrophins. Thus the unoccupied p75NTR appears to exert a tonic inhibition on filopodial length that is released by neurotrophin binding. The action of neurotrophins on p75NTR appears to be mediated by inhibition of RhoA, a GTPase that regulates the actin cytoskeleton. The authors conclude that p75NTR regulates filopodia in both a ligand-dependent and ligand-independent manner.
Phalloidin staining of p75NTR +/+ and p75NTR –/– retinal growth cones in the absence of neurotrophin treatment. See the article by Gehler et al. for details.
Behavioral/Systems/Cognitive
Bursting with Information in Electric Fish Anne-Marie M. Oswald, Maurice J. Chacron, Brent Doiron, Joseph Bastian, and Leonard Maler (see pages 4351-4362)
Virtually all neurons fire trains or bursts of action potentials to transmit information. The critical determinants of this neural code are often difficult to decipher, because sensory inputs are complex and the neural output is variable. Oswald et al. approach this problem using a favorable preparation, electrosensory pyramidal cells in weakly electric fish. These cells receive electroreceptor EPSP, normally fire at 10–20 Hz, and generate bursts of action potentials by backpropagation into the dendrites. The cells encode both low-frequency stimuli related to prey and high-frequency communication signals. Using in vivo and in vitro recording and a simple two-compartment neuronal model, the authors conclude that single spikes and bursts simultaneously encode different “streams” of information. Bursts were biased toward low-frequency events, whereas isolated spikes simultaneously code over the entire frequency range. How these two patterns of information are decoding at higher brain centers in the fish will be interesting to determine.
Neurobiology of Disease
A Narcoleptic Rat Carsten T. Beuckmann, Christopher M. Sinton, S. Clay Williams, James A. Richardson, Robert E. Hammer, Takeshi Sakurai, and Masashi Yanagisawa (see pages 4469-4477)
Many of us experience occasional daytime drowsiness, as dimming the lights during a seminar will reveal. However, this normal experience is in contrast to the debilitating sleep disorder narcolepsy, in which patients drop suddenly, and frequently, from the awake state to brief periods of rapid eye movement (REM) sleep. Recently developed animal models in dogs and mice have suggested that loss of the hypothalamic peptide orexin can mimic the disorder. Mutations in orexin or its receptors do not seem to underlie the human disorder; rather, it appears that hypothalamic orexin-producing neurons may somehow degenerate. Beuckmann et al. have now created a narcolepsy model in the rat that may facilitate physiological studies of narcolepsy. They inserted the cytotoxic gene ataxin-3 under control of the prepro-orexin promoter. Thus, instead of expressing orexin, neurons expressing the transgene gradually degenerated and were absent by 4 months of age. The narcoleptic rats displayed behavioral hallmarks of the disorder, including behavioral arrests with muscle atonia, analogous to cataplexy observed in patients with this disorder.
