PKCδ Enhances Alcohol Effects
Doo-Sup Choi, Weizheng Wei, J. Kevin Deitchman, Viktor N. Kharazia, Heidi M. B. Lesscher, Thomas McMahon, Dan Wang, Zhan-Heng Qi, Werner Sieghart, Chao Zhang, Kevan M. Shokat, Istvan Mody, and Robert O. Messing
(see pages 11890–11899)
Alcohol intoxicates by enhancing GABAA receptor signaling, and accumulating evidence suggests that protein kinase C (PKC) isozymes modulate the effects of alcohol. PKCγ and PKCε have reciprocal modulatory effects: PKCε phosphorylates GABA receptor γ2 subunits, and mice lacking PKCε exhibit greater alcohol-induced enhancement of GABA currents, become more intoxicated, and consume less alcohol than controls; PKCγ knock-out has the opposite effects, but how it exerts these effects is unknown. This week, Choi et al. report that a third PKC isozyme, PKCδ, also modulates alcohol's effects on GABA signaling. PKCδ is co-expressed with GABAA receptor δ subunits in thalamic nuclei that project to motor cortex. Alcohol had less severe behavioral effects (e.g., reduced ataxia and hypothermia) in mice lacking PKCδ, and alcohol's enhancement of tonic GABA currents in thalamic neurons was reduced in knock-out mice. The results suggest PKCδ normally enhances current through extrasynaptic GABA receptors that contain δ but not γ2 subunits.
Photostimulation Can Restore Respiration after Spinal Cord Injury
Warren Alilain, Xiang Li, Kevin P. Horn, Rishi Dhingra, Thomas E. Dick, Stefan Herlitze, and Jerry Silver
(see pages 11862–11870)
Cervical spinal cord injury (SCI) causes respiratory insufficiency, which is the primary cause of death after SCI. Therefore, improving respiration after SCI is an important goal. Respiration is controlled by brainstem neurons that project in the bulbospinal tract and synapse with motor neurons in the ipsilateral phrenic nucleus, which in turn innervate the ipsilateral hemidiaphragm. A latent respiratory pathway comprising contralateral bulbospinal axons that cross in the phrenic nucleus also exists, and activation of this pathway restores respiration. Hoping to activate latent respiratory pathways, Alilain et al. expressed a light-activated ion channel in rat phrenic neurons after spinal hemisection. Subsequent intermittent photostimulation produced rhythmic contraction of the ipsilateral hemidiaphragm. After 3–4 stimulation periods, the ipsilateral hemidiaphragm began to contract synchronously with the contralateral hemidiaphragm, and normal respiration continued for several hours after stimulation ceased. NMDA receptor antagonists prevented this recovery, suggesting that photostimulation produced NMDA-receptor-dependent plasticity of the latent respiratory pathway.
Constant Light Rapidly Resets Circadian Clock
Rongmin Chen, Dong-oh Seo, Elijah Bell, Charlotte von Gall, and Choogon Lee
(see pages 11839–11847)
Travel and irregular work hours disrupt people's circadian rhythms, and returning to an appropriate schedule can take days. Chen et al. now report that exposure to constant light can rapidly reset the circadian clock. Unlike constant darkness, in which circadian rhythms persist, constant light abolishes circadian rhythms. Constant light desynchronizes the activity of suprachiasmatic nuclear neurons that regulate peripheral rhythms and activity. As a result, animals are active for brief epochs throughout a 24 h period. When Chen et al. moved mice from constant light to constant darkness, the circadian behavioral and cellular protein rhythms were restored. Mice immediately became active, and remained active for several hours before entering an extended rest. The timing of activity onset was constant after the second day of total darkness. Transfer to darkness after 28 h of constant light produced a 12 h phase shift—a phase reversal that normally takes 5 d.
Neurobiology of Disease
Cannabinoids Limit Spread of Neuropathic Pain
Ildiko Racz, Xavier Nadal, Judith Alferink, Josep E. Baños, Jennifer Rehnelt, Miquel Martín, Belén Pintado, Alfonso Gutierrez-Adan, Elena Sanguino, Jorge Manzanares, Andreas Zimmer, and Rafael Maldonado
Nerve injury causes inflammation, which leads to neuropathic pain that is characterized by increased sensitivity to painful stimuli (hyperalgesia) and pain in response to normally innocuous stimuli (allodynia). Cannabinoids are one of the few effective treatments for such pain. Using transgenic mice either lacking or overexpressing cannabinoid CB2 receptors, Racz et al. have outlined how cannabinoids regulate neuropathic pain. Overexpression of cannabinoid CB2 receptors in microglia and neurons attenuated neuropathic pain resulting from sciatic nerve injury. In contrast, mice lacking CB2 receptors experienced abnormal contralateral hyperalgesia in addition to the normal ipsilateral pain. These increases or decreases in hyperalgesia were associated with decreased and increased numbers of activated microglia in the spinal cord, respectively. Further experiments suggested that CB2 downregulates interferon-γ-dependent expression of proteins that regulate activation and migration of microglia. Because activated microglia secrete cytokines that sensitize nociceptive sensory neurons, inhibiting their activation and migration limits the spread of neuropathic pain.