Cellular/Molecular
Ethanol and Its Channel Targets
Weizheng Wei, Leonardo Coutinho Faria, and Istvan Mody
(see pages 8379-8382)
Andrzej Z. Pietrzykowski, Gilles E. Martin, Sylvie I. Puig, Thomas K. Knott, Jose R. Lemos, and Steven N. Treistman
(see pages 8322-8332)
Often the best drug can be “dirty” in that it has multiple mechanisms of action. That certainly seems to be true of ethanol, which can act on a number of receptor systems in the brain. This week, two reports zero in on the actions of ethanol on ligand- and voltage-gated ion channels. Wei et al. report that ethanol enhances the tonic GABA current mediated by δ subunit-containing receptors in dentate granule cells, whereas tonic GABA currents containing the α5 subunit in CA1 cells were not enhanced. Pietrzykowski et al. looked at large-conductance, calcium-sensitive potassium (BK) channels in neurohypophysial nerve terminals in explant cultures. The BK channels, which regulate hormone release, were potentiated by ethanol. However, acute potentiation decreased rapidly over minutes, and the current density decreased over 24 hr. The ethanol tolerance appears to result from a decrease in functional channels in the membrane.
Development/Plasticity/Repair
New Interneurons and Olfactory Discrimination
Emeka Enwere, Tetsuro Shingo, Christopher Gregg, Hirokazu Fujikawa, Shigeki Ohta, and Samuel Weiss
(see pages 8354-8365)
With age, the sensory faculties ebb, and smell is no exception. Olfactory interneurons are born throughout life and then make the trek from the subventricular zone (SVZ) to the olfactory bulb. This week, Enwere et al. attempt to link failing odor discrimination to failing neurogenesis of interneurons. Aged mice had fewer newly formed olfactory interneurons as well as impaired fine odor discrimination. Aged mice could distinguish discrete odors such as coconut and almond but had trouble with fine discrimination of similar-smelling mixtures. Bromodeoxyuridine labeling confirmed the reduced proliferation of neurons from the SVZ. Mutant mice with reduced expression of transforming growth factor-α, the primary ligand at the epidermal growth factor receptor (EGFR), displayed a phenotype that mimicked the aged mice. The authors suggest that age-related reduction in EGFR signaling leads to decreased proliferation of olfactory bulb interneurons. In short, they just don't make `em like they used to.
Behavioral/Systems/Cognitive
Opiate-Induced Sensitization of the Locus Ceruleus
Guang-Ping Xu, Elisabeth Van Bockstaele, Beverly Reyes, Thelma Bethea, and Rita J. Valentino
(see pages 8193-8197)
Chronic opiate use results in an array of neurological changes, many of which fuel drug-seeking behaviors. Noradrenergic neurons in the locus ceruleus (LC) contribute to the stress response, an activity that is enhanced by corticotropin-releasing factor (CRF) and reduced by endogenous μ-opioids. This balance, Xu et al. postulate this week, can be upset by chronic opiate use. In rats that received chronic morphine, LC neuron firing was highly sensitized to CRF and to physiological stress attributable to nitroprusside-induced low blood pressure. During swim stress, chronically treated rats tried to climb the chamber walls, whereas normal rats used only the effort necessary to keep afloat. CRF receptor expression did not increase with chronic morphine, but the authors propose that sensitization relies on changes upstream of the formation of cAMP. This action of chronic opiates can enhance responsiveness to stressful stimuli and may thus contribute to continued drug-seeking behaviors.
Neurobiology of Disease
A Painful Sodium Channelopathy
Theodore R. Cummins, Sulayman D. Dib-Hajj, and Stephen G. Waxman
(see pages 8232-8236)
Channelopathies are an important cause of human disease, often those associated with hyperexcitability such as epilepsy. This week, Cummins et al. examine a channelopathy in a rare, dominantly inherited pain disorder called erythermalgia, literally redness of the skin and burning pain in the limbs. Two mutations in a voltage-dependent sodium channel have been identified recently in affected patients. The channel, Nav1.7, is preferentially expressed in dorsal root ganglion neurons, including nociceptors. To examine the function effects of the mutations, the authors expressed the human β1 and β2 subunits along with Nav1.7 in human embryonic kidney 293 cells and made whole-cell recordings from wild-type channels and the I848T and L858H mutants. In mutant channels, activation was shifted to more negative membrane potentials and deactivation was slowed, resulting in large currents in response to slow subthreshold depolarizations. These altered properties are predicted to make nociceptors hyperexcitable, and thus a cause of the pain.