Cellular/Molecular
Gap Junctions Spread Toxic Signals
Abram Akopian, Tamas Atlasz, Feng Pan, Sze Wong, Yi Zhang, et al.
(see pages 10582–10591)
Gap junctions are prevalent in the retina: they are present in all five neuronal classes. Electrical coupling via gap junctions is essential in the rod pathway and is thought to improve signal detection in other pathways. Additionally, gap junctions allow glucose, signaling molecules, and other small molecules to pass between cells. Unfortunately, this coupling can be detrimental, allowing injury in one cell to spread to others. Akopian et al. found that although the apoptosis-inducing molecule cytochrome C is too large to pass through gap junctions, injecting cytochrome C into mouse retinal ganglion cells not only killed the injected cell, but also killed cells coupled to that cell. Furthermore, ischemia and NMDA-induced excitotoxicity caused widespread neuronal death that was attenuated by gap junction blockers. Interestingly, different connexins were affected by different insults: ischemia reduced membrane expression of Cx36, whereas NMDA reduced expression of Cx45. As a result, knocking out Cx36 prevented the spread of excitotoxic cell death, whereas knocking out Cx45 reduced ischemia-related cell death.
Injecting an apoptosis inducer into a single retinal ganglion cell (red) activated apoptosis (indicated by TUNEL labeling, yellow) in coupled cells as well as in the injected cell. See the article by Akopian et al. for details.
Development/Plasticity/Repair
NCAM Helps Reinnervating Axon Terminals Mature
Peter H. Chipman, Melitta Schachner, and Victor F. Rafuse
(see pages 10497–10510)
If some of the nerves innervating a muscle are severed, spared axons innervating the same muscle sprout and reinnervate the denervated area. Because the sprouted axons develop a larger terminal arbor than they had initially, they must produce more synaptic vesicles and distribute them more widely. This process appears to require neural cell adhesion molecule (NCAM). Chipman et al. found that knocking out NCAM selectively in motor neurons prevented functional reinnervation of muscle. During the first week after partial denervation, NCAM-deficient motor axons sprouted and formed the same number of terminal branches and motor endplates as control axons. But unlike control terminals, which matured over the second week, NCAM-deficient terminals remained immature. Synaptophysin-labeled synaptic vesicles occupied a smaller area of the endplates in NCAM-deficient axons than in controls, and vesicles continued to be released at extrasynaptic as well as synaptic sites. As a result, the quantal content of NCAM-deficient motor axons remained low and stimulating the sprouted fibers did not elicit muscle twitches.
Systems/Circuits
Astrocytes Make the Stomach Growl
Gerlinda E. Hermann, Edouard Viard, and Richard C. Rogers
(see pages 10488–10496)
Glucoprivation, typically resulting from fasting, triggers gastric contractions commonly known as hunger pangs. Gastric contractions are driven by neurons in the dorsal motor nucleus of the vagus (DMN), which receive inhibitory input from neurons in the nucleus of the solitary tract (NST). Distension of the stomach leads to increased spiking in the normally quiescent gastric NST neurons, causing a pause in tonically active DMN neurons. This allows the stomach to relax and expand to accommodate more food. Hermann et al. found that the effect of gastric distension on NST neurons was inhibited by injecting 2-deoxy-d-glucose (2DG)—which blocks glucose utilization and thus mimics glucoprivation—into the fourth ventricle. Perhaps by reducing spiking in NST, 2DG increased firing of DMN neurons during both rest and distension, and thus increased gastric motility. More interestingly, however, all effects of 2DG were blocked by injecting fluorocitrate, a glia-specific metabolic inhibitor, into the fourth ventricle. This suggests glucoprivation is sensed by hindbrain astrocytes, which in turn modulate neuronal firing.
Neurobiology of Disease
Lowering Kynurenic Acid Reduces Schizophrenia-Like Deficits
Rouba Kozak, Brian M. Campbell, Christine A. Strick, Weldon Horner, William E. Hoffmann, et al.
(see pages 10592–10602)
Kynurenic acid (KYNA), a molecule derived from tryptophan, is an endogenous inhibitor of NMDA and α7 nicotinic acetylcholine receptors. KYNA levels are elevated in the brain and CSF of schizophrenics, and administration of KYNA to rodents causes deficits in attention, working memory, and sensory gating similar to those occurring in schizophrenia. The endogenous role of KYNA is poorly understood, however. To begin to address this question, Kozak et al. investigated the effects of PF-04859989, a recently discovered inhibitor of kynurenine aminotransferase II (KAT II), which synthesizes most KYNA in the brain. In addition to lowering brain KYNA levels, systemic PF-04859989 attenuated auditory gating deficits induced in rats by amphetamine (which increases dopaminergic signaling) or ketamine (which inhibits NMDA receptors), reduced working memory deficits induced by ketamine, and improved performance on a sustained attention task in the presence of distractors. PF-04859989 also attenuated ketamine-induced impairments in working memory in monkeys. Thus, PF-04859989 may help alleviate these symptoms in schizophrenia.
