Blood Vessels Say NO to Axons
Giti Garthwaite, Katalin Bartus, Denise Malcolm, David Goodwin, Martha Kollb-Sielecka, Chaminda Dooldeniya, and John Garthwaite
This week, Garthwaite et al. identify a nitric oxide (NO) signaling pathway from microvascular endothelial cells to axons. The authors made extracellular "grease-gap" recordings from isolated rat optic nerve in vitro to test components of the pathway. The exogenous NO donor with the intriguing name of PAPA/NO [(Z)-1-N-(3-ammoniopropyl)-N-(n-propyl)-amino]/NO] caused a few millivolt axonal depolarization. Inhibitors of NO synthase hyperpolarized the axons, suggesting that endogenous NO can activate the pathway. The source was endothelial nitric oxide synthase (eNOS) because optic nerves from mice lacking eNOS lacked tonic levels of NO and the associated depolarization. Immunostaining revealed eNOS in microvascular endothelial cells and cGMP in axons. Hyperpolarization-activated cyclic nucleotide-gated channels are a likely, but not necessarily the only, downstream target of NO-generated cGMP. At least under the conditions of these experiments, the pathway showed tonic activity, suggesting a potentially regulatory coupling between capillaries and neural activity.
Life and Death in the Basal Forebrain
Marta Volosin, Wenyu Song, Ramiro D. Almeida, David R. Kaplan, Barbara L. Hempstead, and Wilma J. Friedman
The p75 neurotrophin receptor (p75NTR) and Trk receptor tyrosine kinases elicit opposite cellular consequences: apoptosis and survival, respectively. This week, Volosin et al. compared the actions of proneurotrophins, selective activators of p75NTR, with neurotrophins on basal forebrain neurons. These cholinergic neurons express p75NTR throughout life as well as all three Trk receptors. The results suggest that Trk receptor activation cannot overcome apoptosis triggered by activation of p75NTR in these cells. Forty percent of cultured basal forebrain neurons died after treatment with pro-nerve growth factor (pro-NGF), but not after mature NGF treatment. Pro-NGF-induced apoptosis required p75NTR and its coreceptor sortilin. After kainic acid-induced seizures, pro-NGF was detected in basal forebrain astrocytes, lysates from these animals induced cell death of cultured basal forebrain neurons, and neuronal loss was less in p75−/− mice. In contrast to previous studies in sympathetic ganglion neurons, activation of Trk receptors did not protect against pro-NGF-mediated apoptosis.
Purkinje Cell Activity and Saccadic Adaptation
Robijanto Soetedjo and Albert F. Fuchs
Saccades begin as commands from the cortex and converge on motor neurons under orders from the superior colliculus via the brainstem and cerebellum. These pathways adapt over a lifetime to maintain accurate saccades. This week, Soetedjo and Fuchs asked where those adaptations occur. The authors trained monkeys to focus on jumping targets and evoked adjustments by moving the targets during horizontal saccades. They recorded from Purkinje neurons in the oculomotor vermis, cells that are thought to control saccade amplitude and participate in adaptation. In 21 of the 27 neurons hey recorded, the authors were able to determine a direction preference based on the complex spiking (CS) activity of each neuron. CS activity during adaptation did not reflect the magnitude of the error, but it did reflect the error direction. Errors in the on-direction that required backward adaptation produced greater changes in CS activity than did control saccades or forward adaptation errors.
ATM and DNA Damage Repair
Inbal Dar, Sharon Biton, Yosef Shiloh, and Ari Barzilai
Cellular DNA damage such as double-strand breaks sets off restorative signaling cascades. One of these molecules is the protein kinase ataxia-telangiectasia mutated (ATM). Interestingly, ATM mutations cause abnormalities affecting proliferating cells, including immunodeficiency and an increase in certain cancers, but also cerebellar degeneration. The mechanism of the loss of cerebellar granule cells and Purkinje cells, and thus the ataxia, is not obvious. This week, Dar et al. examined the activation and subcellular localization of ATM in mouse cerebellar neurons. An anti-ATM antibody revealed predominantly nuclear expression of ATM. DNA damage by ionizing radiation induced ATM autophosphorylation, colocalization with a marker of double-strand breaks, and phosphorylation of downstream targets of ATM. The evidence thus suggests that ATM is operating in cerebellar neurons in a fashion in a similar fashion to that in proliferating cells. Thus, failure of DNA repair likely underlies the loss of granule cells and Purkinje cells in ataxia-telangiectasia.
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