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The Journal of Neuroscience, June 9, 2004, 24(23)
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This Week in the Journal
Cellular/Molecular
D5 Goes beyond the Synapse
Constantinos D. Paspalas and Patricia S. Goldman-Rakic
(see pages 5292-5300)
Dopamine and some other neuromodulators are thought to act by volumetric signaling (i.e., gradient diffusion of neurotransmitter to receptors beyond a synaptic release site). In this issue, Paspalas and Goldman-Rakic outline such a signaling pathway involving the D5 dopamine receptor. They used immunogold labeling and electron microscopy in pyramidal neurons of monkey prefrontal cortex. Specific signaling cascades presumably require cytosolic compartmentalization of signaling molecules and a physical scaffold for downstream effector molecules. The authors report a tight anatomical link between membrane D5 receptors in the perisomatic region and subsurface cisterns (SSCs) containing calcium and inositol 1,4,5-trisphosphate (InsP) receptors. SSCs were confined to the perisomatic regions and were not seen in nonpyramidal neurons. Likewise, D5 receptors appeared to be exclusively expressed outside of the synapse. Thus D5 receptors in plasma membrane closely apposed to SSC and mitochondrial membranes provide a plausible mechanism for, as the authors put it, "diffuse" dopaminergic transmission.
Development/Plasticity/Repair
Gene Wakeup Calls from the Locus Ceruleus
Chiara Cirelli and Giulio Tononi
(see pages 5410-5419)
The role of sleep in brain function continues to draw our attention. In addition to the obvious behavioral differences between sleep and waking states, differences in brain function are seen at multiple levels, including gene-expression patterns. The factors dictating gene expression while asleep and awake are unknown but presumably reflect distinct patterns of brain function. Previous studies have revealed both sleep- and wake-associated genes. This week, Cirelli and Tononi examine the role of the central noradrenergic (NA) system on sleep-wake gene-expression patterns. Locus ceruleus neurons widely innervate the cortex and are active during waking but mostly silent during sleep. The authors used the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to selectively remove noradrenergic inputs. Expression of
20% of wake-associated genes decreased with DSP-4 treatment, whereas one sleep-associated gene, translation elongation factor 2, was upregulated. The results are consistent with an important role for NA in the regulation of state-dependent genes.
Behavioral/Systems/Cognitive
Oscillating with a Silicon Neuron and a Heart Interneuron
Michael Sorensen, Stephen DeWeerth, Gennady Cymbalyuk, and Ronald L. Calabrese
(see pages 5427-5438)
The motor pattern generator of the medicinal leech heartbeat is made up of "half-center oscillators" (pairs of mutually inhibitory neurons that alternately fire). Sorenson et al. have now created an oscillator made of one heart interneuron (HN) and one model silicon neuron (SiN), a unique beast like a half-leech, half-robot. The result is a synaptically connected hybrid oscillator that mimics the biological pair. They focused on the role of the hyperpolarization-activated inward current Ih, which influences the pattern of the half-center oscillator. They varied the Ih maximal conductance (
h) and its time course of activation and deactivation in the silicon neuron and also manipulated
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Design of a hybrid half-center oscillator in the leech. An HN in an isolated ganglion preparation was connected via a dynamic clamp to an SiN. The dynamic clamp provided real-time control signals to create artificial synapses between the HN and SiN. See the article by Sorenson et al. for details.
Neurobiology of Disease
Prozac and 5-HT1A Receptor Internalization
Mustapha Riad, Luc Zimmer, Latifa Rbah, Kenneth C. Watkins, Michel Hamon, and Laurent Descarries
(see pages 5420-5426)
Selective serotonin reuptake inhibitors (SSRIs) increase extracellular serotonin, a presumed mechanism for their antidepressant action. However, this apparently simple mechanism is made more complicated by 5-HT1A autoreceptors expressed on the soma and dendrites of serotonergic neurons. These receptors inhibit serotonin release, but they are also subject to desensitization by agonist-dependent internalization. The action of 5-HT1A autoreceptors could underlie the observed delay of several weeks before SSRIs exert their maximal effect in patients. A single dose of a 5-HT1A receptor-specific agonist in rats leads to internalization of autoreceptors in the nucleus raphe dorsalis (NRD) but not of 5-HT1A receptors in hippocampal neurons. Riad et al. sought to determine whether internalization also occurs immediately in response to the SSRI fluoxetine (Prozac). A single injection caused a shift of autoreceptors from plasma membrane to cytosol. Furthermore, autoreceptor internalization could be detected with the 5-HT1A radioligand [18F]MPPF and positron emission tomography, which they propose could be used as a molecular assay of SSRI treatment.
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