Feng et al. describe persistent neuronal microtubule minus end growth that depends on the CAMSAP protein Patronin and is needed for dendritic minus-end-out polarity.
Background Major depressive disorder (MDD) is increasingly recognized to involve functional deficits in both GABAergic and glutamatergic synaptic transmission. To elucidate the relationship between these phenotypes we made use of GABAA receptor γ2 subunit heterozygous (γ2+/−) mice, which we previously characterized as a model animal with construct, face and predictive validity for MDD. Methods To assess possible consequences of GABAergic deficits on glutamatergic transmission we quantitated the cell surface expression of NMDA- and AMPA-type glutamate receptors and the function of synapses in the hippocampus and medial prefrontal cortex of γ2+/− mice. In addition, we analyzed the effects of an acute dose of the experimental antidepressant ketamine on all these parameters in γ2+/− vs. wild-type mice. Results Modest defects in GABAergic synaptic transmission of γ2+/− mice resulted in a strikingly prominent homeostatic-like reduction in the cell surface expression of NMDA- and AMPA-type glutamate receptors, along with prominent functional impairment of glutamatergic synapses in the hippocampus and medial prefrontal cortex (mPFC). A single subanesthetic dose of ketamine lastingly normalized the glutamate receptor expression and synaptic function of γ2+/− mice to wild-type levels, along with antidepressant-like behavioral consequences selectively in γ2+/− mice. GABAergic synapses of γ2+/− mice were potentiated by ketamine in parallel but only in mPFC. Conclusions Depressive-like brain states that are caused by GABAergic deficits involve a homeostatic-like reduction of glutamatergic transmission that is reversible by an acute, subanesthetic dose of ketamine, along with regionally selective potentiation of GABAergic synapses. The data merge the GABAergic and glutamatergic deficit hypothesis of MDD.
Dendrite microtubules are polarized with minus-end-out orientation in Drosophila neurons. Nucleation sites concentrate at dendrite branch points, but how they localize is not known. Using Drosophila, we found that canonical Wnt signaling proteins regulate localization of the core nucleation protein γTubulin (γTub). Reduction of frizzleds (fz), arrow (low-density lipoprotein receptor-related protein [LRP] 5/6), dishevelled (dsh), casein kinase Iγ, G proteins, and Axin reduced γTub-green fluorescent protein (GFP) at branch points, and two functional readouts of dendritic nucleation confirmed a role for Wnt signaling proteins. Both dsh and Axin localized to branch points, with dsh upstream of Axin. Moreover, tethering Axin to mitochondria was sufficient to recruit ectopic γTub-GFP and increase microtubule dynamics in dendrites. At dendrite branch points, Axin and dsh colocalized with early endosomal marker Rab5, and new microtubule growth initiated at puncta marked with fz, dsh, Axin, and Rab5. We propose that in dendrites, canonical Wnt signaling proteins are housed on early endosomes and recruit nucleation sites to branch points. OPEN ACCESS Citation: Weiner AT, Seebold DY, Torres-Gutierrez P, Folker C, Swope RD, Kothe GO, et al. (2020) Endosomal Wnt signaling proteins control microtubule nucleation in dendrites. PLoS Biol 18 (3): e3000647. https://doi.
TRPV ion channels are directly activated by sensory stimuli and participate in thermo-, mechano- and chemo-sensation. They are also hypothesized to respond to endogenous agonists that would modulate sensory responses. Here, we show that the nicotinamide (NAM) form of vitamin B3 is an agonist of a Caenorhabditis elegans TRPV channel. Using heterologous expression in Xenopus oocytes, we demonstrate that NAM is a soluble agonist for a channel consisting of the well-studied OSM-9 TRPV subunit and relatively uncharacterized OCR-4 TRPV subunit as well as the orthologous Drosophila Nan-Iav TRPV channel, and we examine stoichiometry of subunit assembly. Finally, we show that behaviours mediated by these C. elegans and Drosophila channels are responsive to NAM, suggesting conservation of activity of this soluble endogenous metabolite on TRPV activity. Our results in combination with the role of NAM in NAD+ metabolism suggest an intriguing link between metabolic regulation and TRPV channel activity.
The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.
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