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The Journal of Neuroscience, June 16, 2004, 24(24)
This Week in the Journal
Cellular/Molecular
The P/Qs, Rs, and Ns of Endocannabinoid Action
Solange P. Brown, Patrick K. Safo, and Wade G. Regehr
(see pages 5623-5631)
Endocannabinoids are now recognized as ubiquitous retrograde messengers, being released from postsynaptic neurons and acting on presynaptic terminals to decrease transmitter release. This week Brown et al. reexamine the presynaptic effector for this CB1 receptor-mediated regulation. They ruled out an indirect effect of cannabinoids on action potential shape through potassium channels and focused on calcium channels as the gateway for reduced presynaptic calcium influx at cerebellar granule cell-Purkinje cell synapses. To avoid problems with penetration of highly lipophilic cannabinoids in the slice preparation, they preferentially recorded the response of fibers near the cell surface to the synthetic partial agonist WIN55,212-2. They measured Purkinje cell EPSCs and the granule cell presynaptic volley and tracked presynaptic calcium with a low-affinity calcium indicator. The N-type, P/Q-type, and R-type calcium channels all contribute to transmitter release from granule cells. Likewise, the cannabinoids did not play favorites; they inhibited each of the calcium channel subtypes.
Development/Plasticity/Repair
ECS in the Rat and Gene Expression
Nadia M. Tsankova, Arvind Kumar, and Eric J. Nestler
(see pages 5603-5610)
Despite its share of controversies, electroconvulsive shock (ECS) therapy remains an effective treatment for severe depression. How does it work? In this week's Journal, Tsankova et al. look for evidence of chromatin remodeling as a possible mechanism for increased gene expression after ECS. They examined the posttranslational modifications of histones that loosen their grip on DNA when acetylated, exposing promoter sequences to transcriptional machinery. After either acute (single shock) or "chronic" (daily for a week) ECS in rats, chromatin immunoprecipitation up to 24 hr later revealed acetylation of histones H3 and H4. These histones associate with the promoters of c-Fos, BDNF, and CREB, proteins with expression that is altered by ECS. H4 modification was a better indicator of overall gene expression with chronic or acute ECS, whereas H3 acetylation was a more selective sign of BDNF upregulation. However even in this study of just three genes in a limited time frame, the patterns were complex. One senses this is only the beginning of this interesting story.
Behavioral/Systems/Cognitive
Monkeys Are Scared of Snakes too
Ned H. Kalin, Steven E. Shelton, and Richard J. Davidson
(see pages 5506-5515)
Fear and anxiety-related behaviors involve the amygdala in rodents, monkeys, and humans. Yet only in rodents, thus far, have the roles of specific nuclei with the amygdala been assessed. Kalin et al. made asymmetric as well as bilateral excitotoxic lesions in adolescent rhesus monkeys. They focused on the role of the central nucleus of the amygdala (CeA), because it has interconnections with the hypothalamus, basal forebrain, and brainstem. They measured fear by the extra time monkeys took to retrieve a favorite treat from atop a transparent box containing a live, free-moving snake, and by their freezing behavior to a human intruder. Lesioned monkeys showed diminished behavioral fear responses in both assays, consistent with a role of the CeA in fear in monkeys, similar to observations in rodents. Changes in ACTH and CRF also suggested a functional connection between the CeA and the adrenal-pituitary system.
Neurobiology of Disease
Mitochondrial Calcium and Excitotoxic Cell Death
Natalia B. Pivovarova, Huy V. Nguyen, Christine A. Winters, Christine A. Brantner, Carolyn L. Smith, and S. Brian Andrews
(see pages 5611-5622)
Excitotoxic injury to neurons induces both immediate (necrotic) and delayed (apoptotic) death after calcium entry. Mitochondrial damage is an established source of apoptogenic proteins such as cytochrome c. But apoptosis requires ATP, itself the product of functioning mitochondria. Pivovarova et al. provide an explanation for this apparent paradox by examining single mitochondria in cultured hippocampal neurons after NMDA-induced excitotoxicity. They examined the ultrastructural changes to mitochondria with electron microscopy and total mitochondrial calcium (free and bound) using electron probe x-ray microanalysis (EPMA). Although many mitochondria showed reversible increases in calcium and swelling, only a third became overloaded with calcium. These mitochondria were severely swollen with ruptured outer membranes. In contrast, the intact mitochondria retained cytochrome c, indicating that release of the apoptogenic protein was from the damaged mitochondria. The authors suggest that the mix of intact and ruptured mitochondria is a necessary component of apoptotic cell death.
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Neurons, fixed immediately after NMDA stimulation, show both damaged, swollen mitochondria with electron-lucent matrices (arrows) and structurally normal mitochondria (arrowheads). In this high-pressure frozen, freeze-substituted preparation, Ca-rich inclusions are seen in normal and swollen mitochondria. See the article by Pivovarova et al. for details.
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