Neurobiology

Neurobiology

nb95pap.qxd 10/25/1999 8:40 PM Page 501 501 Neurobiology Paper alert A selection of interesting papers that were published in the two months befor...

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Neurobiology Paper alert A selection of interesting papers that were published in the two months before our press date in major journals most likely to report significant results in neurobiology.

mediated mEPSCs, with no effect on NMDA receptors. Viral transfection of the blocking peptide inhibited surface expression of AMPA but not NMDA receptors.

Current Opinion in Neurobiology 1999, 9:501–510

Destabilization of cortical dendrites and spines by BDNF. Horch HW, Kruttgen A, Portbury SD, Katz LC: Neuron 1999, 23:353-364. • Significance: This study reveals with time-lapse two-photon microscopy that dendritic architecture is relatively stable, whereas dendritic spines appear and disappear more dynamically over a time course of many hours. BDNF overexpression changed both the morphology and stability of dendritic branches and spines, suggesting a possible role for neurotrophins in remodeling mature neurons. Findings: BDNF was expressed in cortical pyramidal neurons by particle-mediated gene transfer. BDNF greatly increased sprouting of basal dendrites and caused a loss of dendritic spines. The newly formed dendrites and spines were less stable than those of control neurons.

Contents (chosen by) 501 Neuronal and glial cell biology (Sheng, Qiu and Filbin) 502 Development (Lumsden et al.) 504 Cognitive neuroscience (Mayford, Knowlton and Jackson) 505 Signalling mechanisms (Häusser and Murthy) 507 Sensory systems (Wood, Assad and Liman) 508 Motor systems (Ashe and El Manira) 509 Neurobiology of disease (Brandon and Gage) • ••

of special interest of outstanding interest

Neuronal and glial cell biology Selected by Morgan Sheng Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA

Munc 13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Augustin I, Rosenmund C, Sudhof TC, Brose N: Nature 1999, 400:457-461. •• Significance: This mouse knockout study demonstrates the in vivo importance of Munc 13-1, a presynaptic phorbol-esterbinding protein, in presynaptic neurotransmitter release. Munc 13-1 seems to be required for fusion competence (‘maturation’) of synaptic vesicles at a step after vesicle docking. Most interestingly Munc 13-1 is essential only at a subset of synapses; GABAergic synapses and a subset of glutamatergic synapses are unaffected by the loss of Munc 13-1. Also surprising is that brain development is grossly normal despite major defects in synaptic transmission. Findings: Munc 13-1-deficient mice die at birth with apparently normal brain structure. In Munc 13-1 mutant neurons, there was a marked reduction in evoked excitatory synaptic responses and in the size of the readily releasable vesicle pool, with no change in GABA-mediated transmission, postsynaptic responsiveness, alpha-latrotoxin-stimulated release or synaptic ultrastructure. Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism. Noel J, Ralph GS, Pickard L, Williams J, Molnar E, Uney JB, Collingridge GL, Henley JM: Neuron 1999, 23:365-376. • Significance: N-ethylmaleimide-sensitive fusion protein (NSF) is involved in vesicle fusion and binds to the GluR2 subunit of AMPA receptors. This study indicates that NSF binding to GluR2 is important for surface expression of AMPA receptors, perhaps by facilitating insertion of AMPA receptors into the postsynaptic membrane. Interestingly, loss of NSF interaction causes an apparent all-or-none disappearance of functional AMPA receptors from synapses, as evidenced by reduced frequency of mEPSCs. Findings: In cultured hippocampal neurons, disruption of NSF–GluR2 interaction by a blocking peptide caused a rapid decrease in frequency but not amplitude of AMPA-receptor-

Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Naisbitt S, Kim E, Tu JC, Xiao B, Sala C, Valtschanoff J, Weinberg RJ, Worley PF, Sheng M: Neuron 1999, 23:569582. AND

Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF: Neuron 1999, 23:583592. • Significance: This pair of papers describes a novel family of postsynaptic proteins (Shanks) that provides the first biochemical link between the NMDA receptor/PSD-95 complex and the metabotropic glutamate receptor (mGluR)/Homer complex. In addition, Shank appears to connect postsynaptic glutamate receptors to cortactin, an actin regulatory protein. These studies identify an important organizing protein of the postsynaptic density. Findings: A family of Shank proteins was cloned by yeast twohybrid interaction with GKAP (a PSD-95 binding protein) or Homer (a mGluR-binding protein). Shank is a multidomain protein containing ankyrin repeats, an SH3 domain, a PDZ domain (that binds GKAP), a proline-rich region (that contains binding sites for Homer and cortactin), and a SAM domain (that mediates multimerization). Shank is localized in the PSD in vivo and can crosslink Homer and PSD-95 protein complexes in vitro. The synaptic localization of Shank is secondary to the synaptic targeting of PSD-95 and GKAP. Cortactin redistributes to synapses in response to glutamate stimulation, potentially via a regulated interaction with Shank. Selected by Jin Qiu and Marie T Filbin Hunter College of the City University of New York, New York, USA

Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Brustle O, Jones KN, Learish RD, Karran K, Choudhary K, Wiestler OD, Duncan ID, McKay DG: Science 1999, 285:754-756.

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•• Significance: Describes efficient generation of embryonic stem (ES) cell-derived glial precursors for transplantation; this may have applications for treating human neurological disorder. Findings: The authors successfully generated precursors for oligodendrocytes and astrocytes from ES cells in vitro. Transplantation of these cells in a rat model of a human myelin disease shows that these ES-cell-derived precursors interact with host neurons and efficiently myelinate axons in brain and spinal cord. Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. Lim DA, AlvarezBuylla A: Proc Natl Acad Sci USA 1999, 96:7526-7531. •• Significance: Describes successful reconstitution of adult subventricular zone (SVZ) cell–cell interactions in a culture system free of serum or exogenous growth factors. Provides a greater understanding of the interaction between precursors and astrocytes that may increase the therapeutic potential of SVZ cells and other neural precursors. Findings: The authors demonstrate that extensive in vitro neurogenesis of adult SVZ precursors requires direct contact with astrocytes. Culturing SVZ precursors in conditioned medium on astrocyte membrane preparations or killed astrocyte monolayers did not support the in vitro neurogenesis. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, Sofroniew MV: Neuron 1999, 23:297-308. •• Significance: Suggests that gene targeting can be used to ablate reactive scar-forming astrocytes after injury within a time frame that could have clinical relevance and provides direct evidence that scar-forming astrocytes limit the growth of nerve fibers after CNS injury in vivo. The findings support the view that removal of these cells, or neutralization of the molecules responsible for this effect, will be required for achieving substantial axon regeneration after injury in the mature mammalian CNS. Findings: The authors show that gene targeting can be used to ablate scar-forming astrocytes and demonstrate roles for astrocytes in regulating leukocyte trafficking, repairing the brain–blood barrier, protecting neurons and restricting nerve fiber growth after injury in the adult CNS. Retinal ganglion cells lose trophic responsiveness after axotomy. Shen S, Wiemelt AP, McMorris FA, Barres BA: Neuron 1999, 23:285-295. •• Significance: Demonstrates that the death of retinal ganglion cells (RGCs) after axotomy is caused not solely by the loss of retrograde tropic stimuli but also by a profound loss of trophic responsiveness. Therefore, the promotion of axonal regeneration by providing trophic factors will not be effective unless the trophic responsiveness of the injured neurons and their processes is enhanced simultaneously. Findings: The authors show that depolarization increases cAMP in cultured RGCs sufficiently to enhance their responsiveness and that the trophic responsiveness of developing RGCs in intact retinas depends on physiological levels of activity and cAMP elevation. Responsiveness is lost after axotomy but is restored by cAMP elevation. The death of axotomized RGCs can be prevented if they are stimulated simultaneously by several trophic factors together with cAMP elevation.

Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Sheikh KA, Sun J, Liu Y, Kawai H, Crawford TO, Proia RL, Griffin JW, Schnaar R: Proc Natl Acad Sci USA 1999, 96:7532-7537. • Significance: Demonstrates the importance of complex gangliosides in central myelination and maintaining the integrity of axons and myelin. Findings: The authors report that mice lacking complex gangliosides display decreased central myelination, axonal degeneration in both the central and peripheral nervous systems, and demyelination in peripheral nerves. Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. Sondell M, Lundborg G, Kanje MJ: Neuroscience 1999, 19:5731-5740. • Significance: Suggests that vascular endothelial growth factor (VEGF), by virtue of it stimulatory action on axonal outgrowth, Schwann cell proliferation and angiogenesis, may play an important role in the response to nerve injury. Findings: The authors show that addition of VEGF to explanted adult mouse superior cervical ganglia (SCG) and dorsal root ganglia (DRG) promotes cell survival, axonal outgrowth, and proliferation of Schwann cells. The VEGF receptor flk-1 is present on neurons in the SCG and DRG and on Schwann cells. Blocking the MAPK pathway inhibits the VEGF-induced axonal outgrowth, suggesting that VEGF acts through stimulation of the flk-1 receptor.

Development Selected by Andrew Lumsden, Lori Zeltser, Susan Chapman, Frank Schubert, Jon Gilthorpe and Richard Wingate King’s College London, Guy’s Hospital, London, UK

Eph receptors and ephrins restrict cell intermingling and communication. Melitzer G, Xu Q, Wilkinson DG: Nature 1999, 400:77-81. •• Significance: Provides a molecular basis for the phenomenon of differential affinity, whereby cell populations with complementary expression of Eph receptors and ephrin ligands remain discrete during development and do not mix with their neighbours. Eph–ephrin signalling also results in the loss of gap junctional communication. Interaction at the interface between groups of cells that express these molecules in complementary fashion may thus be important in boundary formation in the developing CNS. Findings: Eph receptors and their ephrin ligands were overexpressed in zebrafish animal cap cells, which normally express neither of these molecules and which normally mix freely with one another. However, when cells expressing the receptor meet cells expressing the ligand, they do not mix. Bidirectional signalling (i.e. reciprocal signalling between the Eph receptor and the transmembrane ephrin ligand) is required to prevent cell intermingling. Unidirectional signalling, through either the receptor or the ligand, is sufficient to restrict the formation of gap junctions. A Sonic hedgehog-independent, retinoid-activated pathway of neurogenesis in the ventral spinal cord. Pierani A, Brenner-Morton S, Chiang C, Jessell TM: Cell 1999, 97:903915.

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• Significance: Postulates a role for retinoic acid signalling in the establishment of interneuron identities in the ventral spinal cord in a Sonic hedgehog (SHH)-independent pathway. Findings: SHH can induce V0 and V1 interneurons at low concentrations, but is inhibitory at higher concentrations. The authors have characterised a signal in paraxial mesoderm that induces a population of Dbx-expressing V0 and V1 interneurons in a co-culture assay. Studies with blocking antibodies and Shh–/– knockout mice demonstrate that the activity is SHHindependent. Addition of retinoids and retinoid receptor antagonists suggest that retinoids in the paraxial mesoderm mediate this parallel signalling pathway. Gli3 is required for Emx gene expression during dorsal telencephalon development. Theil T, Alvarez-Bolado G, Walter A, Ruther U: Development 1999, 126:3561-3571. • Significance: Reports that Gli3, which is normally associated with the SHH signalling pathway, is necessary for Emx gene expression in the dorsal telencephalon in a novel SHH-independent pathway. Findings: The authors present a morphological and molecular analysis of the forebrain defects in the extra toes (Xt1) mouse mutant, which carries a null mutation in the Gli3 gene. Whilst early telencephalic patterning is apparently normal, Emx1 and Emx2 are not expressed in Xt1 mice. The mutants lack structures derived from the dorsal telencephalon and thus may anticipate the unreported phenotype of the Emx1/Emx2 double knockout. This is the first report of a SHH-independent function for Gli3. Giant eyes in Xenopus laevis by overexpression of XOptx2. Zuber ME, Perron M, Philpott A, Bang A, Harris WA: Cell 1999, 98:341-352. • Significance: XOptx2 is a new member of the Six/sine oculis family of homeobox-containing genes. This paper suggests that XOptx2 is an intrinsic repressor, inducing cell proliferation in the eye field, thereby acting as a determinant of eye size. Findings: Reports the overexpression phenotype of XOptx2, which suggests that it acts in determining the rate of retinoblast proliferation and thus the size of the eye. Interference with XOptx2 function reduces eye size, whereas overexpression results in clones of cells double the size of controls. The authors further report that Pax6 is able to act synergistically with XOptx2 to increase eye size, which Pax6 is unable to achieve independently. Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Sussel L, Marin O, Kimura S, Rubenstein JLR: Development 1999, 126:3359-3370. • Significance: Demonstrates that a single transcription factor determines the proportional representation of striatum and pallidum in the basal telencephalon during development. Findings: The authors studied the development of the basal telencephalon in Nkx2.1 mutant mice, in which the striatum is enlarged at the expense of pallidal structures. Analysing regionspecific markers in early embryos, they found that the medial ganglionic eminence (MGE) is initially formed, but rapidly adopts a more dorsal fate, being transformed into the lateral ganglionic eminence, the precursor of the striatum. Furthermore, MGE-derived neurons that normally migrate into striatum and cortex are lacking in the mutant.

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Chimeric axon guidance receptors: the cytoplasmic domains of Slit and Netrin receptors specify attraction versus repulsion. Bashaw GJ, Goodman CS: Cell 1999, 97:917-926. • Significance: Reports that the contrasting effects of attractive versus repulsive cellular behaviour directed by Netrin- or Slit-mediated signalling in axons are defined by the cytoplasmic domains of the cognate receptors. This function appears to be interchangeable. Findings: Frazzled (Fra), the DCC-like Netrin receptor, normally mediates attractive cellular responses in Drosophila axons, whereas the structurally related Slit receptor, Roundabout (Robo), mediates repulsion. Interchanging the intracellular components of the two receptors leads to a switch in the navigation behaviour of axons expressing these chimaeric constructs. Thus, axons expressing a hybrid Fra–Robo transgene (i.e. consisting of the extracellular component of Fra and the intracellular domain of Robo) are repelled by the midline source of Netrin, to which Fra-expressing cells are normally attracted. The opposite effect is generated by the expression of a chimaeric Robo–Fra construct, whereby axons migrate towards a normally repulsive source of Slit. Interestingly, the Fra–Robo gain-of-function phenotype can be suppressed by the overexpression of commissureless (comm), indicating that the normally down-regulatory effect of comm on Robo is mediated via the intracellular domain of Robo. A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts Netrininduced growth cone attraction to repulsion. Hong K, Hinck L, Nishiyama M, Poo M-M, Tessier-Lavigne M, Stein E: Cell 1999, 97:927-941. • Significance: Suggests that the attractive or repulsive response of growth cones to netrin signalling may be determined by the physical interaction between receptors of different classes. Findings: Netrin receptors belonging to the DCC family are thought to mediate attractive axonal responses, whereas those of the UNC5 family are believed to confer repulsive behaviour. This distinction is not clear cut, however, as some neurons that are repulsed by netrins coexpress both Dcc and unc-5 family members. The authors provide evidence that clarifies this situation by manipulating Xenopus spinal axons. Overexpression of UNC5 in these cells converts the normally attractive, DCCmediated effect of netrin-1 to a repulsive one that is also dependent on DCC function. The switch of attraction to repulsion is instigated by the binding of netrin-1 to either receptor, triggering the formation of an UNC5/DCC complex. Homeotic transformation of rhombomere identity after localised Hoxb1 misexpression. Bell E, Wingate RJT, Lumsden A: Science 1999, 284:2168-2171. • Significance: Spatially restricted misexpression of Hoxb1 reveals a precision of Hox gene function that has not previously been observed following either Hox gene mutation or global expression. Findings: Retroviral and microsurgical techniques were used to restrict spatially the overexpression of a single Hox gene (Hoxb1) to subregions within a single branchiomeric segment. Using cranial motor axon projections to gauge the registration between hindbrain segments and branchial arches, the authors show that normal segmental organisation of the head can be systematically re-programmed by targeting expression of Hoxb1 to either motor neurons or target tissue.

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Directional guidance of neuronal migration in the olfactory system by the protein Slit. Wu W, Wong K, Chen J, Jiang Z, Dupuis S, Wu JY, Rao Y: Nature 1999, 400:331-336. AND

Cellular and molecular guidance of GABAergic neuronal migration from an extracortical origin to the neocortex. Zhu Y, Li H, Zhou L, Wu JY, Rao Y: Neuron 1999, 23:473-485. • Significance: Demonstrates that the Slit protein can act in vitro as a chemorepellent for tangentially migrating cells in the forebrain. However, the importance of Slit for the overall organisation of tangential migration in vivo (beyond perhaps an initial ‘push’ in the right direction) remains unclear. Findings: In both studies, identical in vitro methods were used to demonstrate that secreted Slit protein can orient the movement of cells out of respective explants of the anterior subventricular zone (rostral migrating olfactory neurons) and the lateral ganglionic eminence (GABAergic interneurons). For both systems, when migratory pathways were preserved ‘intact’ in cultured slices, exogenous Slit had a general inhibitory effect on cell movement. By contrast, application of the extracellular domain of the Slit receptor, Robo, reduced the response to Slit of cells emerging from explants; presumably as a result of absorption of the Slit ligand.

Cognitive neuroscience Selected by Mark Mayford University of California—San Diego, La Jolla, California, USA

Novelty acquisition is associated with induction of hippocampal long-term depression. Manahan-Vaughan D, Braunewell KH: Proc Natl Acad Sci USA 1999, 96:87398744. •• Significance: Shows that during exploration of a novel environment, the ability to induce long-term depression (LTD) in the rat hippocampus is enhanced. This suggests a relationship between LTD and learning. Findings: Electrodes were chronically implanted in the hippocampus of rats and the ability to induce LTD at CA1 synapses via low-frequency stimulation of the Schaffer collateral pathway was investigated under various behavioral conditions. When low-frequency stimulation was administered while the rat was exploring an unfamiliar environment, the amount of LTD induced was increased compared to stimulation in a familiar environment. In addition, a previous finding showing that exposure to a novel environment reverses previously induced LTP was replicated. Reciprocal interactions between CA3 network activity and strength of recurrent collateral synapses. Bains JS, Longacher JM, Staley KJ: Nat Neurosci 1999, 2:720-726. • Significance: Demonstrates that long-term potentiation (LTP) and long-term depression (LTD) of CA3–CA3 hippocampal synapses can modulate the patterns of spontaneous network activity in the hippocampus. The control of neuronal network properties by alteration in synaptic strength is thought to be the mechanism by which information stored during learning alters behavior during memory recall. Findings: CA3 neurons were studied in rat hippocampal slices in vitro. Under these conditions, CA3 cells do not normally show significant spontaneous activity. When NMDA-dependent LTP was induced by stimulation of CA3 recurrent collaterals, spontaneous bursting was produced. The timing between bursts was reduced by the induction of LTD at these same synapses.

Memory for places learned long ago is intact after hippocampal damage. Teng E, Squire LR: Nature 1999, 400:675-677. •• Significance: Shows that the hippocampus and related medial temporal lobe structures in humans are not necessary for the recall of spatial memories, as had been suggested by some rodent studies. Findings: A patient with severe damage to the hippocampus and surrounding medial temporal lobe structures was examined for spatial and navigational memories of his home town, which he had left almost 50 years earlier. He performed as well as control subjects on these remote spatial memory tasks, although he was severely impaired in similar tasks for more recently learned information. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Bontempi B, Laurent-Demir C, Destrade C, Jaffard R: Nature 1999, 400:671-675. •• Significance: Evidence from metabolic brain imaging is presented to support the notion that the consolidation of long-term memories involves a shift from dependence on the hippocampus to dependence on cortical structures for recall. Findings: Mice were trained in a spatial version of the eight-arm radial maze. At either 5 or 25 days following acquisition of the task, (14C)-2-deoxyglucose uptake was examined during a recall test. The hippocampus was strongly activated during the 5-day but not the 25-day recall test. Conversely, in the 25-day test, the frontal anterior cingulate and temporal cortices were strongly activated relative to their 5-day levels. Selected by Barbara Knowlton University of California, Los Angeles, California, USA

Early neocortical regionalization in the absence of thalamic innervation. Miyashita-Lin EM, Hevner R, Montzka-Wassarman K, Martinez S, Rubenstein JLR: Science 1999, 285:906-909. •• Significance: Demonstrates that the neocortex can develop into specific regions normally in the absence of thalamic innervation. Findings: Neocortical structure was studied in a strain of mutant mice (Gbx-2) that lack thalamic differentiation. On postnatal day 0, these mice exhibited no evidence of thalamocortical projections using retrograde and anterograde tracers, in contrast to normal mice. However, most of the mutant mice exhibited normal cortical morphology, as measured by Nissl staining. In addition, the expression of several genes that demarcate functional neocortical boundaries were completely normal in these mice. Thus, at least early neocortical development can proceed without thalamic input. Selective inhibition of cocaine-seeking behavior by a partial dopamine D3 receptor agonist. Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz J-C, Everitt BJ, Sokoloff P: Nature 1999, 400:371-375. •• Significance: Describes a compound that may be extremely effective in the treatment of stimulant abuse. Findings: The compound BP 897 has been shown to have selective affinity for the D3 receptor in vitro and in vivo. Because D3 receptors have been shown to mediate the reinforcing effects of cocaine, BP 897 was tested for its effects on cocaine-seeking behavior. Rats were trained in a second-order conditioning experiment, in which presentation of a light is paired with an infusion of cocaine administered by a bar press by the rat. The light becomes a conditioned reinforcer that can

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maintain bar pressing for 15 minutes before cocaine is ultimately administered. BP 897 attenuated responding during the light, but not when cocaine was present, indicating that it does not affect the reinforcing effects of cocaine. Rats did not bar press for administration of BP 897, suggesting that it is not reinforcing itself. Because conditioned craving to drug-associated stimuli has been shown to play a major role in substance abuse, this compound could potentially attenuate these cravings without becoming addictive itself or affecting primary reinforcement. Perceptual-motor sequence learning of general regularities and specific sequences. Marsolek CJ, Field JE: J Exp Psychol [Hum Percept Perform] 1999, 25:815-836. • Significance: Suggests that basal-ganglia dependent learning can be independent of specific motor commands yet tied to a particular motor system. These findings help describe the role of the basal ganglia in procedural learning. Findings: Subjects practiced typing a sequence of digits that were generated by a series of rules that governed which digits could follow other digits. Later, they showed faster typing of new sequences that followed the same rules (i.e. general regularity learning). Subjects were even faster when typing sequences on which they had been trained (i.e. sequence-specific learning). These two types of learning were dissociable in that only general regularity learning facilitated performance using a different keyboard configuration, whereas only sequence-specific learning facilitated performance when subjects spoke the strings during training instead of typing them. These results suggest that procedural learning can be broken down into subsystems. Reinforcement enhances hippocampal acetylcholine release in rats: an in vivo microdialysis study. Iso H, Ueki A, Shinjo H, Miwa C, Morita Y: Behav Brain Res 1999, 101:207213. •• Significance: Suggests that the septo-hippocampal pathway may provide a reinforcement signal. Findings: Rats were trained to bar press for food reward in the presence of a discriminative stimulus (a light). Acetylcholine concentrations in the dialysate were elevated over baseline when the discriminative stimulus was present, but not during intervals in which it was not present and no reward was given for bar pressing. This effect was attributed to the presence of reward and not the presence of the discriminative stimulus because there was no elevation in acetylcholine release during a subsequent extinction trial in which the discriminative stimulus was present but bar pressing was not rewarded. Effects of repetition and competition on activity in left prefrontal cortex during word generation. Thompson-Schill SL, D’Esposito M, Kan IP: Neuron 1999, 23:513-522. • Significance: Supports the view that the prefrontal cortex is involved in selecting between competing alternatives. Findings: Eight subjects participated in an fMRI study during which they viewed words and generated appropriate actions (tomato→slice) or colors (milk→white). Subjects are able to respond faster to words that appeared earlier in the task, regardless of which ‘generate’ condition they were in. This priming effect is typically accompanied by a decrease in neural activity measured by fMRI. This decrease was seen in temporal cortex in the present study, but activation in the left inferior frontal gyrus decreased only when the viewed word was in the same generate condition that it had been in during the first

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viewing. Activity actually increased in this region when the generate conditions did not match, even though behavioral performance was facilitated, presumably because competing semantic information was activated. Distinct functional types of associative long-term potentiation in neocortical and hippocampal pyramidal neurons. Buonomano DV: J Neurosci 1999, 19:6748-6754. • Significance: Demonstrates a difference between cortical and hippocampal LTP that may be related to their respective functions. Findings: Using slices from both auditory cortex and hippocampus, short-term plasticity (STP) was generated using paired pulses and trains of stimulation before and after the induction of LTP. In cortical slices, STP was observed in the first EPSP induced at the beginning of the stimulation train, with little potentiation to subsequent pulses. There was also a sharp decrease in the amount of paired-pulse facilitation that could be generated after the induction of LTP compared to before. In contrast, in hippocampal slices, EPSPs occurring later in the stimulation train were potentiated as much as those occurring early in the train. Also, the induction of LTP did not affect the subsequent amount of paired-pulse facilitation. These results suggest functional differences between LTP and STP in these two regions, with cortical STP being more sensitive to stimulus onset. Selected by Stephen Jackson University of Wales, Gwynedd, UK

Manifestation of scotomas created by transcranial magnetic stimulation of human visual cortex. Kamitani Y, Shimojo S: Nat Neurosci 1999, 2:767-771. •• Significance: Transcranial magnetic stimulation (TMS) has received increased interest of late as it is thought to offer cognitive neuroscientists a reversible, ‘virtual lesion’, method for investigating the effects of localised brain dysfunction in humans. However, as the authors point out, the effects of TMS are often difficult to observe directly. This paper reports a study in which location, size, and extent of TMS-induced suppression of visual cortex was made directly observable. Findings: The authors used single-pulse TMS suppression of visual cortex to create an ‘artificial scotoma’. Participants were presented with a large field visual grating pattern that was followed by a single electromagnetic pulse applied, using a figure 8 coil, to a region of the scalp located over the occipital cortex. Under these conditions, participants reported that the patterned visual stimulus appeared to have an area of the pattern missing, and that the ‘missing’ portion of the visual pattern moved systematically with the placement of the TMS coil on the scalp. Using this technique, the authors report spatial and temporal characteristics of TMS-induced suppression of visual cortex.

Signalling mechanisms Selected by Michael Häusser University College London, London, UK

Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Augustin I, Rosenmund C, Südhof T, Brose N: Nature 1999, 400:457-461. •• Significance: Identification of a presynaptic protein that is essential for exocytotic fusion of docked synaptic vesicles at most glutamatergic but not at GABAergic synapses. This pro-

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vides direct evidence that central synaptic vesicles undergo a process of maturation, and indicates that a key step in this process is distinct at excitatory and inhibitory synapses. Findings: Munc13-1 is a brain-specific presynaptic phorbol ester receptor. Munc13-1-deficient transgenic mice die shortly after birth, despite having brains with apparently normal structure and cytoarchitecture. To analyze synaptic transmission, the authors made cultures of hippocampal neurons from mutant neonates. These formed ultrastructurally normal synapses, with no change in the number of docked vesicles. However, transmitter release was substantially impaired at excitatory (but not inhibitory) synapses: release could not be induced by electrical stimulation, calcium ionophores, or by hypertonic sucrose solution, but could be rescued by α-latrotoxin. These findings suggest that Munc13-1 arrests the vesicle maturation cycle after vesicle docking but before fusion competence has been achieved. Interestingly, a subpopulation of excitatory synapses made by single axons functioned normally, indicating heterogeneity of vesicle maturation even at the level of synapses made by the same cell.

θ, a novel γ-aminobutyric acid type A receptor subunit. Bonnert TP, McKernan RM, Farrar S, Le Bourdelles B, Heavens RP, Smith DW, Hewson L, Rigby MR, Sirinathsinghji DJS, Brown N, Wafford KA, Whiting PJ: Proc Natl Acad Sci USA 1999, 96:9891-9896. • Significance: Describes the identification of θ, a new subunit of the GABAA receptor gene family. The θ subunit coassembles with other GABAA receptor subunits to generate a receptor with lower affinity for GABA. The new subunit appears to be expressed predominantly in monoaminergic neurons, particularly the dopamine neurons of the substantia nigra. Findings: The authors isolated and cloned human θ subunit cDNA based on sequence homology with other GABAA receptors. The new subunit shows most similarity with β subunits (50% sequence identity with the β1 subunit) but does not substitute functionally for β subunits. The θ subunit does not get transported to the cell surface when expressed on its own, and therefore requires coassembly with other subunits. Using immunoprecipitation, the authors show that the θ subunit is present in approximately 20% of GABAA receptors in rat striatum, and probably assembles with α2, β1 and γ1 subunits. Coexpression of θ with other subunits in HEK cells does not alter benzodiazepine or barbiturate modulation, but lowers GABA affinity up to fourfold. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Takumi Y, Vania Ramírez-León V, Laake P, Rinvik E, Ottersen OP: Nat Neurosci 1999, 2:618624. AND

Immunogold localization of AMPA and NMDA receptors in somatic sensory cortex of albino rat. Krarzia VN, Weinberg RJ: J Comp Neurol 1999, 412:292-302. • Significance: Direct anatomical demonstration of the colocalization of AMPA and NMDA receptors in the postsynaptic density (PSD) of hippocampal and cortical glutamatergic synapses. At hippocampal CA1 synapses, the ratio between AMPA and NMDA receptors is shown to depend critically on the PSD size, with the ~25% of synapses lacking AMPA receptors but expressing NMDA receptors (corresponding to the ‘silent’ synapses detected electrophysiologically) being smaller than synapses where both receptors were detected. Similar

findings were made at cortical synapses, indicating that synapse size is important for determining the functional properties of a synaptic connection. Findings: The authors used postembedding immunogold methods in conjunction with antibodies selective for NMDA and AMPA receptors to estimate their relative densities at excitatory synapses onto pyramidal cells in hippocampus and cortex. All synapses showed NMDA receptor labelling (except for a subpopulation of cortical synapses), whereas synapses with PSDs less than ~180 nm in diameter were AMPA immunonegative at hippocampal CA1 synapses. Selected by Venkatesh N Murthy Harvard University, Cambridge, Massachusetts, USA

Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Westphal RS, Tavalin SJ, Lin JW, Alto NM, Fraser IDC, Langeberg LK, Sheng M, Scott JD: Science 1999, 285:93-96. • Significance: Shows that a signalling complex containing type I protein phosphatase (PP1) and cAMP-dependent protein kinase A (PKA) is physically attached to NMDA receptors — this might facilitate rapid and specific regulation of channel activity. Findings: NMDA receptors are critical components of synapses, and their regulation has profound effects on synaptic transmission. In this study, the authors demonstrate that yotiao, an NMDA-receptor interacting protein, also binds to PP1 and PKA. Coexpression of NMDA receptors and yotiao in HEK cells resulted in an increased sensitivity of NMDA receptor currents to cAMP analogs (compared to expression of NMDA receptors only). This increased sensitivity required an anchored pool of PKA. Similar experiments using peptides to block the phosphatase activity of PP1 indicated that the regulation by PP1 of NMDA receptors is potentiated by yotiao. Molecular identification of a eukaryotic, stretch-activated nonselective cation channel. Kanzaki M, Nagasawa M, Kojima I, Sato C, Naruse K, Sokabe M, Iida H: Science 1999, 285:882-886. •• Significance: Reports the functional characterization of a yeast gene product Mid1 as a eukaryotic stretch-activated cation channel. Findings: Stretch-activated calcium channels are thought to play a role as mechanotransducers in many cells. The molecular identity of these channels is unknown. In this study, the authors demonstrate that the MID1 gene of yeast encodes an integral plasma membrane protein. Expression of MID1 in Chinese hamster ovary (CHO) cells leads to an increased calcium conductance and calcium influx into cells. Voltage-clamp experiments revealed that the channels are permeable to monovalent and divalent cations, and that calcium blocks monovalent cation currents. Single-channel currents indicated a unitary conductance of 32 picoSiemens. Mechanical stimuli in the form of decreased external pressure (which would stretch the membrane) increased the channel open probability and mean open time. Regulation of DLG localization at synapses by CAMKIIdependent phosphorylation. Koh YH, Popova E, Griffith LC, Budnik V: Cell 1999, 98:353-363. • Significance: Provides genetic evidence that CaMKII modulates the clustering of the synapse-organizing protein Discs large (DLG) at Drosophila synapses. Findings: The numerous components of a synapse are thought to be localized by their interaction with membrane-associated

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guanylate kinases such as DLG. The question of how these scaffold proteins themselves are clustered at the synapse is addressed by this study. The authors show that constitutively active CaMKII causes abnormal localization of DLG — more of it is present extrasynaptically in muscle fibers. Biochemical experiments showed that CaMKII can phosphorylate a conserved serine residue at position 48 of DLG. Transgenic flies expressing EGFP–DLG fusions with the serine residue substituted with alanine to block phosphorylation had even more tightly regulated synaptic localization than controls. Therefore, the authors suggest that phosphorylation of DLG by CaMKII regulates its synaptic localization.

Sensory systems Selected by John N Wood University College London, London, UK

TRP2: a candidate transduction channel for mammalian pheromone sensory signalling. Liman ER, Corey DP, Dulac C: Proc Natl Acad Sci USA 1999, 96:5791-5796. • Significance: The rat vomeronasal organ (VNO) has been found to express high levels of the cation channel TRP2 in sensory microvilli, raising the possibility that pheromone signalling involves a TRP channel. TRP channels have now been implicated in a variety of sensory processes, ranging from vision to perception of noxious heat. Findings: Degenerate PCR was used to identify TRP-like channels in the rat VNO. Using Northern blots and immunocytochemistry, the authors found the expression of TRP2 to be remarkably specific to sensory microvilli, and proposed a possible role for TRP2 in pheromone signalling, in analogy to the roles of other TRPs in sensory transduction. The G protein Galphai2 is also implicated in pheromone signalling and is also expressed in some VNO neurons. Interestingly, the human TRP2 gene is non-functional. Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia. Ma Q, Fode C, Guillemot F, Anderson DJ: Genes Dev 1999, 13:17171728. •• Significance: This extension of earlier studies on the formation of cranial sensor ganglia suggests that neurogenins 1 and 2 play an important role in determining the fate of functional subsets of trunk sensory neurons. Findings: Large-diameter sensory neurons that express trkB and trkC in dorsal root ganglia (DRG) are born a day before the small-diameter damage sensors that express trkA. Analysis of null mutant mice suggests that bHLH transcription factors neurogenin 1 or 2 are necessary for the formation of DRG sensory neurons, but neurogenin 2 is required principally for the generation of trkB and trkC neurons, whilst the trkA population is dependent upon the expression of neurogenin 1. These observations provide evidence that neurogenins may play a role both in neurogenesis and in subsequent cell fate specification for trunk sensory neurons. Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. Cesare P, Dekker LV, Sardini A, Parker PJ, McNaughton PA: Neuron 1999, 23:617624. • Significance: Presents evidence of a role for a single specific PKC isoform in the sensitisation of heat-sensing neurons to bradykinin (BK).

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Findings: BK enhances the membrane ionic current activated by heat in nociceptive neurons, using a pathway that involves activation of protein kinase C (PKC). Five PKC isoforms are present in sensory neurons, but only PKC-epsilon is translocated to the cell membrane by BK. Heat sensitisation is blocked by a pseudosubstrate inhibitor of PKC epsilon, whilst injection of constitutively activate PKC-epsilon causes sensitisation. This suggests a speciifc role for a single PKC isoform in modulating the sensitivity of nociceptive neuorns to noxious heat responses. Isolectin B(4)-positive and -negative nociceptors are functionally distinct. Stucky CL, Lewin GR: J Neurosci 1999, 19:6497-6505. • Significance: Adult damage-sensing neurons fall into two populations that depend on NGF or GDNF as trophic factors. This paper provides evidence for functional differences in noxious heat perception by the two types of neurons. Findings: Whole-cell voltage and current-clamp recordings were carried out on acutely isolated adult mouse dorsal root ganglion neurons that were labelled with fluorescent IB(4). These neurons have longer-duration action potentials, higher densities of TTX-resistant sodium currents, and smaller noxious heat-activated currents than IB(4)-negative neurons. NGF, but not GDNF, increases the number of neurons that respond to noxious heat. The different electrophysiological properties expressed by IB(4)-positive and -negative small neurons, including their different heat sensitivities, indicate that they may relay distinct aspects of noxious stimuli to the CNS. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED: Nature 1999, 400:452-457. • Significance: The noxious heat receptor VR-1 is gated by low pH and capsaicin. This paper provides evidence for another endogenous ligand, the cannabinoid anandemide. Findings: Anandemide was found to cause vasodilation via release of CGRP. Because capsazepine blocks this effect, and cannabinoid receptors antagonists for CB1 and CB2 subtypes are without effect, the authors suggest that the effect is mediated through actions on the capsaicin receptor VR-1. Exogenously expressed VR-1 is indeed activated by anandemide. These observations support an important role for VR-1 in integrating a variety of signals that modulate nociceptor activity in the periphery. Selected by John A Assad Harvard Medical School, Boston, Massachusetts, USA

Neural correlates of decision variables in parietal cortex. Platt ML, Glimcher PW: Nature 1999, 400:233-238. • Significance: Provoking study suggesting that decision variables such as potential reward for an animal can influence the response of parietal neurons. Findings: Recordings were made from neurons in the lateral intraparietal area (LIP) of monkeys trained to use a cue to guide a saccadic eye movement toward one of two visual targets, one of which was placed within the response field of the neuron under study. The relative reward (volume of juice) given to the animals for successfully completing an eye movement toward one or the other target was varied systematically among blocks of trials. Neuronal responses to the onset of the target within the response field increased systematically when a subsequent eye movement to that target yielded the bigger reward of the

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two possible eye movements. This suggests that decision variables such as reward contingency may indirectly influence parietal neurons, most probably by biasing the animals to cast their attention or plan eye movements toward the more rewarded target. Auditory cortical responses in the cat to sounds that produce spatial illusions. Xu L, Furukawa S, Middlebrooks JC: Nature 1999, 399:688-691. • Significance: Interesting demonstration that the responses of cortical auditory neurons to a class of auditory stimuli that create a spatial illusion correlate with the perceived spatial location of the illusory stimuli. Findings: The auditory system uses several cues for localizing sound sources, among them the spectral filtering caused by the head and external ears for perceiving elevation of the source. Thus, observers often mistakenly mislocalize the elevation of narrow-band filtered sounds. The authors recorded from area A2 neurons in anesthetized cat, first using broad-band stimuli at varying elevations to determine the spatial tuning characteristics of the neurons, and then using narrow-band stimuli. Narrow-band stimuli were consistently ‘mislocalized’ by the neurons to elevations consistent with the measured filtering characteristics of the external ears of the animals as a function of elevation. These responses may be the basis for the perceptual spatial illusion caused by narrow-band sound sources. Topography of contextual modulations by short-range interactions in primary visual cortex. Das A, Gilbert CD: Nature 1999, 399:655-661. • Significance: Intriguing study suggesting that the seemingly indiscriminate selectivity of local interconnections in primary visual cortex can produce varied and sophisticated short-range contextual visual modulation. Findings: Optical maps of orientation selectivity were made from the primary visual cortex of anesthetized cats. Pairs of closely spaced neurons were recorded from identified orientation columns to assess their mutual connectivity using cross-correlation analysis. Connection strength between two neurons was a graded function of their separation, irrespective of difference in preferred orientation between the two sites. This suggests a nonspecific radial spread of local influence from neurons, consistent with the radially symmetric pattern of local axonal arborization of cortical pyramidal neurons. However, suppressive modulation of responses by orthogonally oriented stimuli placed just outside, but flanking the classical receptive field was dependent on the preferred orientation of the flanking site as well as its cortical separation. This suggests that neurons could be subject to local contextual modulation in very different and sophisticated ways, depending upon whether the local gradient of preferred orientation is smooth or abrupt. Selected by Emily R Liman Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA

Functional identification of a goldfish odorant receptor. Speca DJ, Lin DM, Sorensen PW, Isacoff EY, Ngai J, Dittman AH: Neuron 1999, 23:487-498. •• Significance: Reports the cloning of a fish odorant receptor that is structurally related to putative pheromone receptors from the mammalian vomeronasal organ and suggests a broader role for this family of receptors in odorant transduction.

Findings: This paper reports the expression cloning from a goldfish olfactory cDNA library of an odorant receptor for basic amino acids. The receptor (named 5.24) has nanomolar affinity for arginine and lysine and couples to phosphatidyl inositol turnover in heterologous expression systems. Receptor 5.24 is expressed in a subset of olfactory neurons that are likely to be the microvillous cells and, thus, analogs of mammalian vomeronasal neurons. Remarkably, receptor 5.24 is unrelated in primary sequence to mammalian odorant receptors, but is instead related to a family of putative pheromone receptors from the mammalian vomeronasal organ. Optical imaging of odorant representations in the mammalian olfactory bulb. Rubin BD, Katz LC: Neuron 1999, 23:499-511. •• Significance: Presents a powerful method for visualizing electrical activity in the mammalian olfactory bulb and provides new insights into odorant information coding. Findings: Intrinsic signal imaging, which relies on inherent activity-dependent changes in optical properties of tissue, was used to visualize responses of the rat olfactory bulb to odorant stimulation. Remarkably strong signals were obtained in circumscribed areas that probably reflected activity in individual glomeruli. Different odorants activated different patterns of activity, with structurally similar odorants eliciting more similar patterns of activity. These data support a model in which olfactory information is encoded in the mammalian olfactory bulb by spatial patterns of activity.

Motor systems Selected by James Ashe Brain Sciences Center, VAMC, Minneapolis, Minnesota, USA

Neural correlates of decision variables in parietal cortex. Platt ML, Glimcher PW: Nature 1999, 400:233-238. •• Significance: The data suggest that the classic sensory–motor reflex of Sherrington is not an adequate model for the interpretation of sensory–motor processes in the cerebral cortex. Rather, cells in parietal cortex, at the interface between sensation and action, are correlated with decision variables best explained by a decision-theoretic model of behavior. Findings: Monkeys were instructed to make saccadic eye movement in one of two directions in response to a visual stimulus. Over successive trials, either the probability of a particular instructed direction or the volume of the juice reward for each direction was varied. Cells in the lateral intraparietal cortex were modulated both by the probability of reward and the magnitude of that reward. When the animals were allowed to freely choose a response, both the behavior and the neuronal activity were correlated with the relative gain of a particular response. Reach plans in eye-centered coordinates. Batista AP, Buneo CA, Snyder LH, Andersen RA: Science 1999, 285:257-260. • Significance: There is an ongoing debate regarding the coordinate framework in which arm movements are represented in the parietal cortex. The results presented here suggest that reaching movements may be represented in eye-centered coordinates. However, there is a certain ambiguity about this, in that the only definitive conclusion that can be made from the data is that the target of the movement is represented in relation to the eye. Whether the reaching movement in also planned in the same co-ordinate frame remains an open question.

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Findings: Neuronal recordings were made in a portion of the parietal cortex thought to be specialized for arm reaching while a monkey made reaches to targets specified either in eye-centered or in limb-centered coordinates. In general, the spatial tuning of the cells was insensitive to changes in the limb-centered positions of the targets but not to changes in the direction of gaze. Real-time control of a robot arm using simultaneously recorded neurons in the motor cortex. Chapin JK, Moxon KA, Markowitz RS, Nicolelis MAL: Nat Neurosci 1999, 2:664-670. • Significance: The exciting aspect of this work is that it suggests neural signals can be ‘trained’ in real-time to change their relation to one aspect of a behavior (e.g. movement) to another (e.g. reward). An obvious potential benefit of this finding would be in the application of such a approach in patients with paralysis in order to control external devices or their own muscles. However, much work remains to be done given the complexity of human movement when contrasted with the simple onedimensional behavior tested in this experiment. Findings: Rats were trained to move a lever with the forepaw to control the position of a robot arm that delivered a fluid reward while chronic neuronal recordings were made from cells in the motor cortex and motor thalamus. Simultaneous recordings from up to 30 single cells were conditioned to produce a neuronal population signal that predicted the lever movement. These brainderived signals were then used to control the robot arm (which had been mechanically uncoupled from the paw lever) in realtime. The animals reduced or stopped the lever movement but the neuronal population signal continued to drive the robot arm. Selected by Abdel El Manira Karolinska Institute, Stockholm, Sweden

Laser ablations reveal functional relationships of segmental hindbrain neurons in zebrafish. Liu KS, Fetcho JR: Neuron 1999, 23:325-335. •• Significance: Provides an elegant demonstration that serially repeated hindbrain neurons form functional groups that control escape behavior in zebrafish. Findings: In vertebrates, successive hindbrain segments contain morphologically similar reticulospinal neurons forming serially repeated arrays of cells. One such set is the Mauthner array, which consists of three repeated reticulospinal neurons and is thought to produce different forms of the escape response in fish. The present study used cell-specific laser ablation techniques to determine whether the segmental hindbrain cells in the Mauthner array form a functional group. Ablation of all three cells eliminated escape responses to both head- and tail-directed stimuli. Killing the Mauthner cell impaired escape responses from tail-directed but not from head-directed stimuli. The results of this study thus show that serially repeated reticulospinal neurons in the Mauthner array form a functionally related group. Neuronal pacemaker for breathing visualized in vitro. Koshiya N, Smith JC: Nature 1999, 400:360-363. •• Significance: Although the neural network generating the respiratory rhythm has been localized in a functionally identified subregion (called the pre-Bötzinger complex) in the lower brainstem, the neuronal mechanisms underlying the rhythmic activity has not been investigated. This study demonstrates that the respiratory network consists of pacemaker neurons coupled by excitatory synaptic interactions that synchronizes their activity.

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The results represent an important step towards understanding the organization of the respiratory network. Findings: This study used electrophysiological and imaging techniques in rat brainstem slices to investigate the organization of the respiratory network. Rhythmically active fluorescent neurons were located in a region that corresponds to the preBötzinger complex. After blockade of non-NMDA glutamatergic transmission by CNQX, some neurons continue to burst rhythmically but asynchronously. The bursting frequency of these pacemaker neurons depends on the membrane potential. The results thus show that the neuronal network generating rhythmic respiratory activity consists of synaptically coupled pacemaker neurons and that the frequency of bursting depends on the baseline membrane potential. Coordination of fast and slow rhythmic neuronal circuits. Bartos M, Manor Y, Nadim F, Marder E, Nusbaum MP: J Neurosci 1999, 19:6650-6660. •• Significance: Explores the cellular mechanisms underlying interactions between neuronal circuits. This study shows that a specific intercircuit synapse is pivotal for determining the coordination between two circuits in the crab stomatogastric ganglion (STG). Findings: The crab STG contains two distinct but interacting circuits. These circuits generate a slow (gastric mill) and a fast (pyloric) rhythm. During an ongoing pyloric rhythm, stimulation of an identified modulatory projection neuron activates the gastric mill motor pattern. It is shown that an identified synapse from the pyloric circuit onto the gastric mill circuit is essential for determining the gastric mill burst frequency and the coordination between the two circuits. The results thus indicate that intercircuit synapses can enable an oscillatory circuit to control the speed of a slower oscillatory circuit. Shunting versus inactivation: analysis of presynaptic inhibitory mechanisms in primary afferents of the crayfish. Cattaert D, El Manira A: J Neurosci 1999, 19:6079-6089. • Significance: Two mechanisms, based on simulation studies, have been proposed to account for presynaptic inhibition in sensory afferents: a shunting mechanism and inactivation of sodium channels. This study analyzes the relative importance of these two mechanisms and shows that shunting represents the primary mechanism for presynaptic inhibition. Findings: Anatomical and electrophysiological techniques were used in an in vitro preparation of the crayfish to analyze the relative importance of shunting mechanisms versus sodium channel inactivation in mediating presynaptic inhibition of sensory transmission. GABAergic synaptic inputs mediating presynaptic inhibition were located on the main axon before it branches. In this region, small-amplitude GABA-mediated primary afferent depolarizations (PADs) produced a marked reduction of action potential amplitude, whereas depolarization of the membrane potential by current injection had no effect. The results thus show that PADs mediate presynaptic inhibition primarily through shunting mechanisms to modulate reflex responses.

Neurobiology of disease Selected by Eugene P Brandon and Fred H Gage The Salk Institute, San Diego, California, USA

Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming reactive astrocytes in adult transgenic mice. Bush TG, Puvanachandra N, Horner

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CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, Sofroniew MV: Neuron 1999, 23:297-308. •• Significance: While it is well established that reactive astrocytes hypertrophy and proliferate in response to CNS injury, the functions of these cells have remained largely unknown. This study reveals functions of reactive astrocytes by eliminating them in transgenic mice. Findings: To ablate reactive astrocytes, mice carrying a thymidine kinase transgene driven by a glial promoter were treated with ganciclovir. Following forebrain stab injury, the absence of reactive astrocytes resulted in excessive edema and leukocyte infiltration, prolonged blood–brain barrier compromise, potentiated neuronal death, and facilitated neurite growth at the site of injury. Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Brustle O, Jones KN, Learish RD, Karram K, Choudhary K, Wiestler OD, Duncan ID, McKay RDG: Science 1999, 285:754-756. AND

‘Global’ cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. Yandava BD, Billinghurst LL, Snyder EY: Proc Natl Acad Sci USA 1999, 96:7029-7034. • Significance: Transplanted stem cells are shown to myelinate axons in myelin-deficient rodents, representing an important step towards the prospect of treating human demyelinating disorders with cell transplants. Findings: Brustle et al. differentiated mouse embryonic stem (ES) cells into oligodendroglial precursors in vitro by culturing them in defined media including factors such as FGF2, EGF, and PDGF. ES-derived precursors that were transplanted into the dorsal columns of myelin proteolipid protein deficient (md) rats formed myelin sheaths. Yandava et al. intraventricularly transplanted clonal neural stem cells originally derived from neonatal mouse cerebellum into newborn shiverer (shi) mice, which lack myelin basic protein. Transplanted cells differentiated into myelinating oligodendrocytes, and treated animals did not suffer the behavioral decline typical of shi mice. Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein. Huang J, Kim LJ, Mealey R, Marsh HC Jr, Zhang Y, Tenner AJ, Connolly ES Jr, Pinsky DJ: Science 1999, 285:595-599.

• Significance: Demonstrates that ischemic neurons express C1q, the protein that initiates the classical pathway of complement activation. Blockade of complement activation is shown to improve recovery indices in an animal model of stroke. Findings: Mice that were treated with soluble complement receptor-1 (sCR1) to block complement cascade initiation showed less neutrophil and platelet accumulation, reduced infarct volume, and improved behavioral recovery following middle cerebral artery occlusion and reperfusion. Results were further improved when a sialylated version of sCR1 was used to additionally inhibit selectin-mediated cellular adhesion. β attenuates Alzheimer-disImmunization with amyloid-β ease-like pathology in the PDAPP mouse. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P: Nature 1999, 400:173-177. • Significance: Suggests immunization against Alzheimer’s disease (AD) may be possible. Findings: The AD-like neuropathology normally seen in transgenic mice expressing human amyloid precursor protein was significantly reduced when animals were immunized once a month with human Aβ42 peptide. An established Aβ plaque burden was also observed to be reduced in animals immunized as adults. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Lu P-J, Wulf G, Zhou XZ, Davies P, Lu KP: Nature 1999, 399:784-788. • Significance: Reports that sequestration of the prolyl isomerase Pin1 may be important in the etiology of tau-related neurodegenerative disorders such as AD and familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Findings: Cdc-2-kinase-mediated hyperphosphorylation of tau reduces its affinity for microtubules and may facilitate its assembly into the paired helical filaments found in neurofibrillary tangles (NFT). Here, it is shown that Cdc-2 phosphorylated tau binds Pin1 both in vitro and in vivo. Pin1 levels are reduced in the soluble fraction of AD brains, and Pin1 accumulates in NFT in AD. Pin1 also facilitates the binding of Cdc-2 phosphorylated tau to microtubules.