Neurobiology

529

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.

constructs markedly reduce neurite outgrowth in cultured cortical neurons. Cables, Abl and Cdk5 form trimolecular complexes at the periphery of postmitotic neurons.

Current Opinion in Neurobiology 2000, 10:529–538

Area identity shifts in the early cerebral cortex of Emx2–/– mutant mice. Mallamaci A, Muzio L, Chan C-H, Parnavelas J, Boncinelli E: Nat Neurosci 2000, 3:679-686. • Significance: This study, together with a similar recent work by Bishop et al. (Science 2000, 288:344-349), suggests that cortical areas are in large part established by gradients of expression of homeodomain transcription factors, resembling the mechanisms involved in the specification of the antero-posterior axis in the Drosophila embryo. Findings: The homeodomain transcription factor Emx2 is expressed in a graded manner by cortical progenitors, at high level by postero-medial cells and low level by antero-lateral cells. The authors have analysed the developing cortex of Emx2 knockout mice by using area-specific or area-restricted markers (Id3, Cad6, Lamp, p75, H-2Z1 transgene) and by tracing the thalamo-cortical connections with DiI. They conclude that loss of Emx2 function results in a marked reduction of posteromedial cortical areas that normally express high levels of Emx2 and a positional shift and/or expansion of the antero-lateral cortical areas that express lower levels of Emx2. The molecular mechanisms that should support this model need to be elucidated and many other outstanding questions regarding cortical development remain unanswered.

Contents (chosen by) 529 Development (Lumsden, Costandi and Ensini) 529 Cognitive neuroscience (Mayford, Hamann and Reber) 531 Signalling mechanisms (Häusser and Murthy) 531 Sensory systems (Wood and Liman) 533 Neuronal and glial cell biology (Sheng) 533 Motor systems (Ashe, Chafee and El Manira) 535 Neurobiology of behaviour (Goodwin and Kyriacou) 536 Neurobiology of disease (Brandon, Gage, Kempermann

and Winkler) • ••

of special interest of outstanding interest

Development Selected by Andrew Lumsden, Moheb Costandi and Monica Ensini King’s College London, Guy’s Hospital, London, UK

Repulsive axon guidance: Abelson and Enabled play opposing roles downstream of the Roundabout receptor. Bashaw GJ, Kidd T, Murray D, Pawson T, Goodman CS: Cell 2000, 101:703-715. • Significance: Identification of the first downstream molecules in the Robo signalling pathway, important in the formation of commissures. Findings: Interaction between Slit and the Roundabout receptor (Robo) causes a repulsive response in the growth cone. Genetic and biochemical evidence reveals that both Abl (Abelson) tyrosine kinase and its substrate Ena (Enabled) interact with Robo. A 50% dosage reduction of Ena leads to a phenotype similar to that of Robo mutants, as does Abl overexpression. Abl antagonizes Robo by phosphorylation of juxtamembrane tyrosine residues. Cables links Cdk5 and c-Abl and facilitates tyrosine phosphorylation, kinase upregulation and neurite outgrowth. Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu C-L, Lanier LM, Gertler FB, Vidal M, Van Etten RA, Tsai LH: Neuron 2000, 26:633-646. • Significance: Provides evidence that cyclin-dependent kinases have functions other than regulation of the cell cycle — namely, a role in actin polymerization in the axonal growth cone. Findings: Neurite outgrowth requires cytoskeletal rearrangements and cell-cycle regulators have been shown to be involved. The Cables protein interacts with cyclin-dependent kinase 5 (Cdk5) in vitro. Abl phosphorylates Cdk5 at the conserved Y15 residue and at other sites, and phosphorylation stimulates kinase activity. Anti-phosphotyrosine antibodies bind to Cables only when it is co-transfected with active Abl. Cdk5 and Abl interact only when Cables is present, suggesting that it might function as an adaptor molecule. Antisense Cable

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

Upregulation of cAMP response element-mediated gene expression during experience-dependent plasticity in adult neocortex. Barth AL, McKenna M, Glazewski S, Hill P, Impey S, Storm D, Fox K: J Neurosci 2000, 20:4206-4216. • Significance: This is the first demonstration that a cAMPmediated transcriptional response may be a critical component of the cortical plasticity associated with sensory deprivation. Findings: The sensory information that mice receive through the whiskers has a somatotopic representation in the barrel cortex. Removal of all but a single whisker leads to an expansion of the spared whisker’s representation. This type of whisker trimming was found to increase transcription of a lacZ reporter via the cAMP response element (CRE). The CRE-mediated transcription was rapid and limited to layer IV neurons of the spared whisker’s representation. Prolonged activation of cAMP-dependent protein kinase during conditioning induces long-term memory in honeybees. Müller U: Neuron 2000, 27:159-168. •• Significance: This is a particularly strong set of data that supports a role for cAMP activation in the formation of long-term memories. Findings: A simple form of Pavlovian conditioning in honeybees, the proboscis extension reflex (PER), requires structures in the antennal lobes (ALs). The authors show that only conditioning protocols that produce long-term memory of the PER result in an increase in cAMP in the ALs. Moreover, when a

530

Paper alert

weak training protocol that normally produces only short-term memory is paired with rapid application of cAMP to the ALs, a long-term memory is produced. Maternal care, hippocampal synaptogenesis and cognitive development in rats. Liu D, Diorio J, Day JC, Francis DD, Meaney MJ: Nat Neurosci 2000, 3:799-806. •• Significance: This is the clearest demonstration to date of an effect of maternal care on adult learning and memory. In addition, the paper provides a possible molecular explanation for these effects. Findings: Female rats were divided into two groups on the basis of whether they provided high or low levels of maternal care. The pups from low-care mothers were impaired on spatial learning as adults, but this impairment could be reversed by crossfostering the pups with a mother providing high levels of care. The low levels of care were associated with a reduction in expression of a number of plasticity-related markers such as NMDA receptors, brain-derived neurotrophic factor and synaptic markers. The change in expression of synaptic markers could also be reversed by crossfostering. Social amnesia in mice lacking the oxytocin gene. Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT: Nat Genet 2000, 25:284-288. • Significance: Demonstrates a requirement for the neuropeptide oxytocin in social recognition memory but not in several other forms of memory. Findings: The ability of a mouse to recognize and remember a previously encountered animal is a strong and ethologically relevant form of memory. Male mice lacking the oxytocin gene completely lack this form of social recognition memory. However, the mice perform normally on several other memory tasks such as olfactory habituation and spatial learning. Selected by Stephan Hamann Emory University, Atlanta, Georgia, USA

Prefrontal-temporal circuitry for episodic encoding and subsequent memory. Kirchhoff BA, Wagner AD, Stern CE: J Neurosci 2000, 20:6173-6180. • Significance: The first clear demonstration that the same brain regions that are sensitive to stimulus novelty are involved in the encoding processes that determine whether an event will be subsequently remembered. Findings: Encoding a new memory for an event has previously been shown to involve the prefrontal cortex and the medial temporal lobes. Newly experienced (novel) stimuli have also been shown to engage these two brain regions more than familiar stimuli. However, it has been unclear whether the same regions which are sensitive to novelty are also the regions which are critical for successfully encoding an event into memory. This study examined brain activity during encoding of pictures and words and investigated whether brain activity during encoding predicted whether that item would be successfully remembered on a subsequent recognition memory test in which subjects discriminated studied items from other, nonstudied items. Novelty was manipulated by presenting either the same item repeatedly during scanning (familiar condition) or a series of new items (novel condition). Novelty-related activations were found in multiple frontal and temporal regions, with words showing a predominantly left-lateralized pattern and pictures showing a more bilateral pattern. Importantly, brain activity during encoding for items that were later successfully recognized

was greater in the same regions that were activated by novelty. These findings are consistent with a number of memory theories that maintain that novelty detection is an integral initial stage in determining whether an event will be encoded into memory. Novel stimuli should engage memory-encoding processes more than familiar stimuli because novel stimuli are not already represented in memory. A neural basis for general intelligence. Duncan J, Seitz RJ, Kolodny J, Bor D, Herzog H, Ahmed A, Newell F, Emslie H: Science 2000, 289:457-460. • Significance: This is the first study to examine the correlates of general intelligence using functional neuroimaging. Findings: The concept of intelligence has long been controversial. Some theorists have favored the notion of a single general intelligence factor or ‘g factor’ that underlies performance on a diverse set of cognitive tasks, whereas others have favored the alternative notion of multiple intelligence factors which are domain specific (e.g. verbal intelligence verses musical intelligence). The goal of this study was to examine the neural basis of the hypothesized ‘g-factor’ by examining brain activity using positron emission tomography (PET). The regional brain activity of subjects was scanned while they performed a variety of cognitive tasks. Each task was part of a pair of tasks, one of which involved complex reasoning, and the other of which was a control task that involved little or no reasoning but was otherwise very similar to the reasoning task. The complex reasoning tasks were hypothesized to engage general intelligence processes to a greater extent than the control tasks. Brain activity in the highreasoning and low-reasoning tasks was contrasted, revealing a selective pattern of activation bilaterally in the lateral frontal cortex. These findings were interpreted as indicating that general intelligence depends most critically on a limited network of frontal regions, rather than reflecting the diffuse recruitment of a number of brain areas as some theories had predicted. A number of aspects of this study are problematic, some of which are pointed out in the accompanying commentary by Sternberg (Science 2000, 289:399-401). However, this study is highly notable as the first attempt to examine this major facet of human cognition using neuroimaging. Selected by Paul J Reber Northwestern University, Evanston, Illinois, USA

Effects of visual experience on the representation of objects in the prefrontal cortex. Rainer G, Miller EK: Neuron 2000, 27:179-186. • Significance: A new, experience-dependent neural correlate of learning to perceive objects is identified in prefrontal cortex from electrophysiological responses to familiar and novel objects. Findings: Monkeys learned to perform a delayed match-tosample (DMS) task using objects that could be degraded to varying degrees to control the amount of object information available on each trial. Both familiar and novel objects were matched effectively when full object information was available, but, with degraded images, matching familiar objects was performed more effectively than matching novel objects. Electrophysiological recordings of neural activity in the frontal lobe indicated reduced levels of activity for the familiar objects compared with novel, but the neurons responding to familiar objects exhibited a more selectively tuned pattern of activity and communicated information about object identity even when the stimulus was severely degraded. These results indicate that

Paper alert

as a stimulus becomes familiar, the neural representation shifts from a broad response to a small, optimally tuned response that is less susceptible to noise, enabling more effective interactions with the environment. Five plus two equals yellow. Dixon MJ, Smilek D, Cudahy C, Merikle PM: Nature 2000, 406:365. • Significance: A patient is reported who experiences a consistent, involuntary difference in conscious perception: synaesthesia for colors to numeric stimuli. This report, in which the effect of synaesthesia is examined in several studies, lays the groundwork for using the study of such altered perceptual experiences to gain insight into the famously difficult problem of the objective, scientific study of consciousness. Findings: A synaesthete, C, reports a consistent experience of specific colors for specific numeric stimuli. This color experience affects perception in a manner that creates interference in color naming when incongruent numeric stimuli are present or when a simple arithmetic statement implies a specific numeric concept. The consistent, automatic nature of the synaesthetic experience suggests that it reflects a robustly different conscious perception. Further understanding of the neural changes that lead to this unusual subjective experience may eventually provide real insight into the neural representation of conscious experience.

Signalling mechanisms Selected by Michael Häusser* and Venkatesh N Murthy† *University College London, London, UK † Harvard University, Cambridge, Massachusetts, USA

Calcium sensitivity of glutamate release in a calyx-type terminal. Bollmann JH, Sakmann B, Borst JGG: Science 2000, 289:953-957. AND

Intracellular calcium dependence of transmitter release rates at a fast central synapse. Schneggenburger R, Neher E: Nature 2000, 406:889-893. •• Significance: The authors perform direct measurements of the sensitivity of fast transmitter release to intracellular calcium in a CNS presynaptic terminal. The results indicate that the presynaptic calcium sensors have a surprisingly high affinity for calcium, and require peak concentrations in the low micromolar range to elicit physiological release. Findings: The authors introduced calcium indicators and photolysable calcium chelators into the large synaptic terminals of the calyx of Held in the brainstem using patch-clamp recording while simultaneously monitoring transmitter release by recording from the postsynaptic neuron. Uncaging calcium caused a uniform increase in calcium concentration in the terminal, allowing direct measurement of the calcium concentrations that trigger release. By comparing release rates in response to presynaptic action potentials and calcium jumps, the authors concluded that single action potentials cause calcium signals which peak at 5–25 µM and which do not saturate the calcium sensors. Action potential-evoked Ca2+ signals and calcium channels in axons of developing rat cerebellar interneurones. Forti L, Pouzat C, Llano I: J Physiol 2000, 527:33-48.

531

• Significance: These studies provide direct evidence from two different neuronal types that single action potentials invade the axonal arborization with high reliability. Findings: The authors filled neocortical layer 2/3 pyramidal neurons and cerebellar interneurons in slice preparations with calcium indicators using somatic patch-clamp recording. Action potential invasion into the axonal arborization was monitored by imaging the spread of calcium signals. In both neuronal types, single action potentials reliably triggered calcium increases even in distal axonal branches, downstream from multiple branchpoints, when hyperpolarizing steps preceded action potential initiation. Interestingly, the axons of cerebellar interneurons displayed calcium hotspots, only a minority of which corresponded to presynaptic varicosities. Timing-based LTP and LTD at vertical inputs to layer II/III pyramidal cells in rat barrel cortex. Feldman DE: Neuron 2000, 27:45-56. • Significance: Describes a bidirectional form of associative synaptic plasticity in neocortical pyramidal neurons where the sign of plasticity depends on the relative timing of single action potentials (APs) and excitatory postsynaptic potentials (EPSPs). The time window is longer for long-term depression (LTD) than for long-term potentiation (LTP). As a consequence, EPSPs uncorrelated with APs become depressed. This strengthens the mounting evidence for associative learning rules based on precise EPSP–AP timing in the CNS. Findings: This is an elegant study which examines NMDAreceptor-dependent plasticity at the vertical inputs to layer 2/3 pyramidal cells from layer 4 neurons in slices of rat barrel cortex. Pairing single APs with EPSPs results in LTP when EPSPs precede APs, and LTD when EPSPs follow APs. As the timing window for LTD (~50 ms) is longer than for LTP (~15 ms), pairing of random EPSPs with APs within a 100 ms time window causes a net depression of the EPSP.

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

Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Pesquero JB, Araujo RC, Heppenstall PA, Stucky CL, Silva JA Jr, Walther T, Oliveira SM, Pesquero JL, Paiva AC, Calixto JB et al.: Proc Natl Acad Sci USA 2000, 97:8140-8145. •• Significance: Provides the first demonstration that bradykinin may act through B1 receptors in the spinal cord to regulate activity-dependent facilitation of pain pathways is presented. Findings: Bradykinin B1 knockout mice were found to be healthy, fertile, and normotensive. Under normal conditions, they are analgesic in behavioral tests of chemical and thermal nociception. Using an in vitro preparation, functional B1 receptors were shown to be present in the spinal cord, and their activation facilitated a nociceptive reflex. Furthermore, a reduction in the activity-dependent facilitation (wind-up) of nociceptive spinal reflexes was observed. Thus, the kinin B1 receptor plays a physiological role in the modulation of spinal cord plasticity that underlies the central component of pain processing. The B1 receptor therefore represents a useful pharmacological target for the treatment of pain.

AND

Action potentials reliably invade axonal arbors of rat neocortical neurons. Cox CL, Denk W, Tank DW, Svoboda K: Proc Natl Acad Sci USA 2000, 97:9724-9728.

FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A,

532

Paper alert

Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ et al.: EMBO J 2000, 19:4046-4055. • Significance: A new family of proteins implicated in inflammatory processes has been identified which antagonises the actions of nerve growth factor (NGF). Findings: A novel 9.4 kDa cysteine-rich secreted protein, FIZZ1 (found in inflammatory zone-1), was found in inflamed murine pulmonary tissue. FIZZ1 is the founding member of a new gene family including two other murine genes expressed in intestinal crypt epithelium and white adipose tissue, and two related human genes. In control mice, FIZZ1 mRNA and protein expression occur at low levels. During allergic pulmonary inflammation, FIZZ1 expression markedly increases in hypertrophic, hyperplastic bronchial epithelium and is also detected in type II alveolar pneumocytes. In vitro, recombinant mFIZZ1 inhibits the NGF-mediated survival of rat embryonic day 14 dorsal root ganglion (DRG) neurons and NGF-induced calcitonin gene-related peptide (CGRP) expression in adult rat DRG neurons. In vivo, FIZZ1 may modulate the function of neurons innervating the bronchial tree, thereby altering the local tissue response to allergic pulmonary inflammation. Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X2/3 receptor signaling in capsaicin-insensitive primary afferent neurons. Tsuda M, Koizumi S, Kita A, Shigemoto Y, Ueno S, Inoue K: J Neurosci 2000, 20:RC90. AND

Diinosine pentaphosphate: an antagonist which discriminates between recombinant P2X(3) and P2X(2/3) receptors and between two P2X receptors in rat sensory neurones. Dunn PM, Liu M, Zhong Y, King BF, Burnstock G: Br J Pharmacol 2000, 130:1378-1384. • Signficance: The authors demonstrate for the first time pharmacological evidence of a role for P2X2/3 receptors in the development of mechanical allodynia. In the accompanying paper, a useful antagonist for distinguishing the involvement of P2X3 and P2X/3 receptors is described. Findings: Injection of alpha,beta-methylene ATP (alphabetameATP), an agonist to P2X1 and 3 receptors, produces mechanical allodynia along with previously described nocifensive behavior and thermal hyperalgesia. This allodynic response was blocked by pretreatment with the P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate. Interestingly, only the mechanical allodynia evoked by alphabeta-meATP selectively remained in neonatal capsaicin-treated adult rats that had selectively lost capsaicin-sensitive neurons. It is suggested that activation of heteromeric P2X(2/3) receptors in peripheral terminals of capsaicin-insensitive primary afferent fibers leads to the induction of mechanical allodynia. In the second paper, diinosine pentaphosphate (Ip[5]I) has been shown to block homomeric P2X3 receptors but not heteromeric P2X2/3 receptors in an Xenopus oocyte expression system. This reagent should prove useful in analysing the respective contribution of P2X3 and P2X2/3 receptors to the development of mechanical allodynia. Selected by Emily R Liman University of Southern California, Los Angles, CA, USA

An olfactory sensory map in the fly brain. Vosshall LB, Wong AM, Axel R: Cell 2000, 102:147-159. AND

Convergent projections of Drosophila olfactory neurons to specific glomeruli in the antennal lobe. Gao Q, Yuan B, Chess A: Nat Neurosci 2000, 3:780-785. •• Significance: These papers demonstrate that, despite differences between flies and mammals in the primary amino acid sequence of odorant receptors, the organization of the olfactory system has been remarkably conserved throughout evolution. Convergent projections of olfactory sensory neurons expressing the same receptor, similar to that seen in mice, have now been visualized in D. melanogaster, allowing the power of fly genetics to be directed towards the study of axonal guidance in the olfactory system. Findings: Recent identification of odorant receptors from D. melanogaster has provided a valuable tool for understanding the organization and function of the fly olfactory system. Vosshall et al. have now completed the identification of D. melanogaster odorant receptors: the total number, at 57 genes, is much smaller than the number of odorant receptors in the genome of the mouse (approximately 1000). Both groups use the identified receptors to show that, as in the mammalian olfactory system, sensory neurons expressing the same receptor converge on the same glomerulus. Vosshall et al. produce a comprehensive mapping of these projections for all 57 receptors, as well as mapping the expression of each gene in the antenna. Some differences between the fly and the mammalian olfactory system are apparent from this work, most notably the observation that the fly odorant receptors do not show allelic exclusion. Mutually exclusive expression of odorant receptor transgenes. Serizawa S, Ishii T, Nakatani H, Tsuboi A, Nagawa F, Asano M, Sudo K, Sakagami J, Sakano H, Ijiri T: Nat Neurosci 2000, 3:687-693. • Significance: This report demonstrates that when two nonallelic copies of the identical odorant receptor and its regulatory region are present in the mouse genome, a stochastic and mutually exclusive choice will be made in the expression of odorant receptor. Findings: Through a mechanism that is still mysterious, olfactory neurons express a single receptor from among the ~1000 odorant receptors present in the genome. To identify regulatory regions of an odorant receptor, the authors used large fragments of YAC (yeast artifical chromosome) DNA to create transgenic mice expressing exogenous copies of the odorant receptor, MOR28 (main olfactory receptor 28), and a biscistronically encoded marker gene. Fragments of YAC DNA greater than 200 kb were necessary to recapitulate the expression pattern of the native receptor. Remarkably, when two copies of the transgene (with different markers) were present in a single animal, only one of the two copies was expressed by individual sensory neurons. Thus it is concluded that genomic alterations, rather than soluble transcription factors, are likely to dictate receptor choice. Ultrasensitive pheromone detection by mammalian vomeronasal neurons. Leinders-Zufall T, Lane AP, Puche AC, Ma W, Novotny MV, Shipley MT, Zufall F: Nature 2000, 405:792-796. •• Significance: The vomeronasal organ (VNO) in mammals detects pheromones that regulate reproductive and social behavior. The authors now demonstrate that at the initial stage of processing – transduction by the vomeronasal sensory neurons — pheromones are detected with exquisitely high sensitivity and specificity.

Paper alert

Findings: Using a combination of electrophysiology and confocal calcium imaging, the authors examined the responses of mouse vomeronasal neurons to six behaviorally characterized pheromones. A small percentage of cells responded to each pheromone, as expected by the similarly low percentage of cells that express each gene encoding a putative pheromone receptor. Remarkably, sensory neurons responded to concentrations of pheromone as low as several picomolar, generating trains of action potentials and a calcium influx. This makes pheromone reception in mammals similar to that in insects, which is famed for its high sensitivity.

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

Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. Nakayama AY, Harms MB, Luo L: J Neurosci 2000, 20:5329-5338. • Significance: Rho and Rac small GTPases have been implicated in the development of neurites and dendritic spines in developing neurons, but it has been unclear whether they play a role in the dynamic regulation of dendritic branching and dendritic spine morphology that occurs in mature neurons. This study indicates that Rho family GTPases function in the maintenance of dendritic spines and dendrite branching even in neurons that have already established dendritic arborization and formed dendritic spines. Findings: Hippocampal slice cultures were biolistically transfected with dominant-negative mutants of Rac and Rho. Dominant-negative Rac1 caused a progressive elimination of dendritic spines in pyramidal neurons. Activated RhoA resulted in a pruning of dendritic branches that was dependent on activity of ROCK (Rho-associated kinase) protein kinase, a downstream effector of Rho. GRASP-1: a neuronal RasGEF associated with the AMPA receptor/GRIP complex. Ye B, Liao D, Zhang X, Zhang P, Dong H, Huganir RL: Neuron 2000, 3:603-617. • Significance: The multi-PDZ protein GRIP (glutamate receptor interacting protein) binds to AMPA receptors and is required for synaptic targeting of AMPA receptors, but its cellular roles are not precisely understood. This study identifies a novel GRIP-associated protein (GRASP1) that functions as a guanine nucleotide exchange factor (GEF) for Ras and that might function in NMDA-receptor-dependent regulation of AMPA receptor distribution. Findings: GRASP1 was identified by yeast two-hybrid screening and interacts with the seventh PDZ domain of GRIP. GRASP1 was found to have GEF activity for Ras in vitro, to be partially localized in synapses in vivo, and to inhibit the dendritic clustering of AMPA receptors when overexpressed in cultured neurons. The subcellular distribution of both AMPA receptors and GRASP1 was dispersed by glutamate stimulation of neurons. Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation and neurite outgrowth. Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu CL, Lanier LM, Gertler FB, Vidal M, Van Etten RA, Tsai LH: Neuron 2000, 26:633-646. • Significance: Cyclin-dependent kinase 5 (Cdk5) is a serine-threonine kinase important for neurite extension and

533

neuronal migration. The non-receptor tyrosine kinase c-Abl has multiple functions in cell physiology and nervous system development. This paper identifies a novel protein Cables (Cdk5 and Abl enzyme substrate) that interacts with both Cdk5 and Abl and that might mediate crosstalk between these two kinase signaling pathways. Findings: Cables was isolated by yeast two-hybrid screen with Cdk5, and associates with Cdk5 in brain lysates. Cables also binds to the SH3 domain of c-Abl and is a substrate of c-Abl. Cables enhances the tyrosine phosphorylation of Cdk5 by c-Abl on tyrosine 15, which stimulates Cdk5 activity. Inhibition of Cables expression by an antisense oligonucleotide reduced, whereas c-Abl increased, neurite outgrowth in neurons. A trafficking checkpoint controls GABA(B) receptor heterodimerization. Margeta-Mitrovic M, Jan YN, Jan LY: Neuron 2000, 27:97-106. • Significance: Functional expression of GABA(B) receptors on the cell surface requires the heterodimerization of GB1 and GB2 subunits of this G-protein-coupled receptor. This study provides a beautiful explanation for this requirement by identifying a retention motif in GB1 that prevents surface targeting of this subunit. The retention motif is masked by interaction with GB2. Findings: An –RXRR- sequence motif was identified in the carboxy-terminal tail of GB1 that inhibits surface expression of GB1. This motif (which is reminiscent of the –RKR- ER retention motif found in certain ATP-sensitive potassium channels) lies at the end of a predicted coiled-coil that mediates GB1 and GB2 heterodimerization. Coiled-coil interaction between GB1 and GB2 ‘masks’ the retention signal, thereby leading to surface targeting of the heteromeric receptor. Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. Zhang Y, Moheban DB, Conway BR, Bhattacharyya A, Segal RA: J Neurosci 2000, 20:5671-5678. • Significance: Nerve growth factor (NGF) promotes both survival and differentiation of PC12 cells. This study shows an interesting dissociation of the biological responses mediated by internalized versus cell-surface NGF receptors (Trk receptors). Active Trk receptors within endosomes promote neuronal differentiation, whereas activated Trk receptors at the cell surface promote survival. Findings: A temperature-sensitive dominant-negative mutant of dynamin (ts-dynamin) was used to prevent internalization of Trk receptors. Inhibition of receptor internalization by ts-dynamin enhanced NGF-dependent survival of PC12 cells, but reduced neurite outgrowth in response to NGF. Internalization was correlated with a distinct pattern of tyrosine phosphorylation of Trk receptor and with a shorter duration of activation of the MAP (mitogen-activated protein) kinase pathway.

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

Covariation of primate dorsal premotor cell activity with direction and amplitude during a memorized-delay reaching task. Messier J, Kalaska JF: J Neurophysiol 2000, 84:152-165. • Significance: There is extensive evidence from behavioral studies that distance and direction are processed independently by the motor system. However, the results of this study indicate that, at least at the level of the dorsal premotor cortex, distance

534

Paper alert

is not independent of direction. Numerous investigators who have surveyed neural activity in other cortical areas over the past decade have also failed to find a significant proportion of cells related to distance alone. The discrepancy between the findings regarding coding of distance and direction at the behavioral and neural levels has yet to be resolved. Findings: Extracellular recordings were made in the dorsal premotor cortex (PMd) while monkeys performed a task in which both the amplitude and direction of spatial targets were held in memory for a short period before the monkey was required to reach. During the delay period, the majority of cells reflected the processing of both distance and direction; few cells were modulated by direction, while none related to distance alone. Persistence of motor adaptation during constrained, multijoint, arm movements. Scheidt RA, Reinkensmeyer DJ, Conditt MA, Rymer WZ, Mussa-Ivaldi FA: J Neurophysiol 2000, 84:853-862. •• Significance: A remarkable characteristic of the motor system is its ability to rapidly adapt motor commands to changing environmental conditions. For example, when unanticipated loads are encountered that cause a limb to deviate from the intended trajectory, joint torques and muscle forces are quickly adjusted so that the original trajectory is recovered within a few attempts. Motor adaptation of this type may either reflect adjustments made to control limb kinematics (trajectory), or dynamics (muscle forces and joint torques). By imposing experimental conditions that partially dissociate these variables, this study provides evidence that deviation from the desired trajectory recruits rapid motor adaptation. Deviation from the forces necessary to produce the desired (straight) trajectory also leads to adaptation, but over a dramatically slower time course. Findings: Human subjects moved a cursor toward a target on a video display by moving a robot manipulandum. The manipulandum applied a force perpendicular to the direction of the subjects’ movement, who learned to make straight movements within this force field by generating an opposing perpendicular force. Normally, adaptation to a force field is revealed after its removal when subjects persist in generating compensatory forces that produce abnormal trajectories. In the present case this was prevented after removal of the perpendicular force field by the application of a ‘channel constraint’ force field that allowed movement of the manipulandum only within a narrow straight path leading directly to the target. The magnitude of the perpendicular force generated by the subject against the walls of this constraint was measured. Under these conditions, the effects of motor adaptation to the perpendicular force field were slow to disappear after its removal, and subjects continued to produce an opposing perpendicular force against the wall of the constraint for more than 100 trials. If trials without any force field were interleaved with trials having the channel constraint, subjects were free to produce abnormal trajectories, and the perpendicular forces generating them quickly disappeared. Multielectrode evidence for spreading activity across the superior colliculus movement map. Port NL, Sommer MA, Wurtz RH: J Neurophysiol 2000, 84:344-357. • Significance: From previous work attempting to reconstruct population dynamics from single neuron recordings, contradictory evidence existed as to whether a ‘moving hill’ of neural activation swept across the surface of the superior colliculus during saccade generation. By simultaneously recording from pairs of neurons in the rostral and caudal portions of the

colliculus, this study obtained direct evidence for a front of neural activation moving toward the rostral colliculus immediately before and during saccade execution. The functional importance of this population dynamic is not yet known. Findings: Simultaneous recordings were made from a pair of electrodes positioned within the rostral and caudal superior colliculus, and a search was conducted for neurons at each electrode that were active during horizontal saccades. Once such a pair of neurons was found, monkeys made a series of saccades ranging in size from 3° to 60° along the horizontal meridian, and the timing of neural activation at the two recording sites was assessed. Across the population of neuronal pairs studied, and in the case where large saccades were made, activation appeared first at the caudal electrode and arrived at the rostral electrode more than 30 ms later. Most (but not all) of the individual neuron pairs showed the same pattern. The data support the time-delayed activation of different portions of the collicular saccade map during saccade execution. Selected by Abdel El Manira Karolinska Institute, Stockholm, Sweden

Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Iwasato T, Datwani A, Wolf AM, Nishiyama H, Taguchi Y, Tonegawa S, Knöpfel T, Erzurumlu RS, Itohara S: Nature 2000, 406:726-731. •• Significance: Provides novel results showing that cortical NMDA receptors are essential for the aggregation of layer IV cells into barrels and for development of the full complement of thalamocortical patterns. Findings: In rodents, the trigeminal and dorsal column pathways convey information about the somatosensory map from the periphery to the neocortex via relay stations in the brainstem and the ventrobasal thalamus. At each level, presynaptic afferents and their targets establish a pattern array (called barrels in the cortex). This study uses mice in which deletion of the gene for NMDAR1 receptor subunits is restricted to excitatory cortical neurons. The results show that sensory-related patterns develop normally in the brainstem and thalamus, whereas in the cortex the array arrangement does not display a distinct pattern. Thus, the aggregation of layer IV cells into barrels depends on postsynaptic NMDA receptor activation. Transformation from temporal to rate coding in a somatosensory thalamocortical pathway. Ahissar E, Sosnik R, Haidarliu S: Nature 2000, 406:302-306. •• Significance: Provides evidence that spatial and temporal coding of external information can be processed separately by two parallel pathways. Findings: The anatomical connections from the whiskers to the rodent somatosensory cortex form two parallel pathways (lemniscal and paralemniscal). The results of this study show that temporally encoded information is decoded by the paralemniscal system, whereas spatially encoded information is decoded by the lemniscal pathway. Thus temporal and spatial information is processed by separate pathways encoding temporal and spatial inputs respectively. Role of inspiratory pacemaker neurons in mediating the hypoxic response of the respiratory network in vitro. Thoby-Brisson M, Ramirez JM: J Neurosci 2000, 20:5858-5866. • Significance: This paper provides the first demonstration that pacemaker inspiratory neurons underlie the increase in respiratory frequency in response to hypoxia. This study also provides further

Paper alert

evidence for the existence of a strict separation between rhythmand pattern-generating mechanisms in the respiratory network. Findings: This study uses a mouse brain-slice preparation containing the functional respiratory network to determine the types of neurons that are responsible for the increase in respiratory frequency in response to hypoxia. The results show that only the activity of pacemaker neurons is modulated by hypoxia, whereas non-pacemaker inspiratory and expiratory neurons are not affected. This provides evidence that the change of respiratory frequency during hypoxia is mediated through pacemaker neurons.

Neurobiology of behaviour Selected by Stephen Goodwin* and Bambos Kyriacou† *University of Glasgow, Glasgow, UK †U niversity of Leicester, Leicester, UK

Molecular identification of a taste receptor gene for Trehalose in Drosophila. Ishimoto H, Matsumoto A, Tanimura T: Science 2000, 289:116-119. • Significance: Ishimoto et al. present evidence suggesting that some taste receptors may be members of the large family of G-protein-coupled transmembrane receptors that are known to detect specific odours. Findings: Using a differential screening strategy, Ishimoto et al. identified a taste receptor gene, Tre1, which controls taste sensitivity to the sugar trehalose in Drosophila melanogaster. The Tre1 gene encodes a protein with similarity to G-protein-coupled seven-transmembrane receptors and is expressed in taste sensory cells. Fly lines carrying severe mutations of the Tre1 gene exhibited reduced taste sensitivity to trehalose, whereas sensitivities to other sugars remained unaltered. Taste sensitivity to trehalose was rescued in Tre1 mutants by overexpressing a wild-type copy of the Tre1 gene. The authors propose that the Tre1 gene encodes a bona fide taste receptor for trehalose in Drosophila melanogaster. Social amnesia in mice lacking the oxytocin gene. Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT: Nat Genet 2000, 25:284-288. •• Significance: Suggests that the hormone oxytocin (OT) performs a key role in the ability of male mice to remember female mice with whom they have had social contact. OT appears to be essential for the development of social memory in mice and suggests that at least some social memories may be represented by unique forms of olfactory memory. Findings: The development of social attachment in rodents depends principally on smell and is crucial for reproductive success. The neurohypophyseal hormones, oxytocin (OT) and vasopressin (AVP), seem to modulate a range of maternal and sexual behaviors. Previous pharmacological studies indicate that AVP may improve social memory, whereas OT can either inhibit or facilitate social memory. Ferguson et al. took male mice that lack the oxytocin gene (Oxt–/–) and introduced the same female mice to them four times, at 10 min inter-trial intervals. Unlike their wild-type (Oxt+/+) counterparts, which show a reliable decrease in olfactory investigation of females in repeated trials, mutant males spent about the same amount of time familiarising themselves with the females, suggesting that they had no memory of the previous encounters. These behavioural differences are not a consequence of defects in general olfactory responses, as both olfactory foraging and olfactory habituation tasks are normal in mutant mice. The observed memory defect appears to be reasonably specific, because spatial memory and behavioural

535

inhibition measured in a Morris water-maze, Y-maze, or habituation of an acoustic startle also seemed normal. Administration of OT, but not of AVP, rescued social memory in mutant mice, and treatment with an OT antagonist induced a social amnesia-like effect in wild-type mice. Impaired cued and contextual memory in NPAS2-deficient mice. Garcia JA, Zhang D, Estill SJ, Michnoff C, Rutter J, Reick M, Scott K, Diaz-Arrastia R, McKnight SL: Science 2000, 288:2226-2230. • Significance: The authors present evidence that the transcription factor neuronal PAS domain protein 2 (NPAS2) is involved in a specific type of long-term memory associated with fear-based tasks. Enticingly, the NPAS2 protein shares structural similarities to a major regulatory protein, CLOCK, involved in circadian rhythms; the authors speculate that NPAS2 may link specific memories with rhythmic gene expression. Findings: NPAS2 is a mammalian transcription factor selectively expressed in the central nervous system. NPAS2 is a member of the basic helix-loop-helix (bHLH) PAS domain family of transcription factors. Garcia et al. generated a mutant mouse strain with a specific deletion in the NPAS2 gene. NPAS2-deficient mice behave normally in a wide variety of behavioural tests but exhibit a moderate deficit in the long-term memory arm of the cued and contextual fear task. The authors speculate that NPAS2 conceivably regulates genes required for the incorporation of long-term memory. Prolonged activation of cAMP-dependent protein kinase during conditioning induces long-term memory in honeybees. Müller U: Neuron 2000, 27:159-168. •• Significance: Demonstrates that persistent activation of cAMP-dependent protein kinase (PKA) induces long-term memory (LTM) in olfactory learning in the honeybee. Findings: In the honeybee, associative olfactory conditioning of the proboscis extension response (PER) induces distinct memories, depending on the number of conditioning trials. For example, single-trial conditioning induces a short-term memory of several days, whereas multiple trials induce a stable LTM. In a series of elegant experiments, Müller measured the temporal dynamics of PKA activity in the antennal lobes (ALs) of honeybees, following induction by specific olfactory conditioning trials. In the ALs — anatomical sites previously implicated in associative learning in honeybees and Drosophila — a prolonged PKA activation is induced by multiple conditioning trials, which induce LTM, but not by a single trial. Moreover, the author was able to artificially prolong the activation of PKA induced during a single trial and this gave rise to long-term memory. Finally, Müller augmented earlier work from his laboratory, showing that nitric oxide synthase (NOS) activity is necessary for LTM formation. nalyot, a mutation of the Drosophila Myb-related Adf1 transcription factor, disrupts synapse formation and olfactory memory. DeZazzo J, Sandstrom D, de Belle S, Velinzon K, Smith P, Grady L, Del Vecchio M, Ramaswami M, Tully T: Neuron 2000, 27:145-158. • Significance: Mild disruptions of the essential transcription factor gene, Adh distal factor-1 (Adf1), affect the molecular mechanisms of developmental and behavioural plasticity in Drosophila melanogaster. Findings: In a behavioural screen for olfactory memory mutants in Drosophila, the authors isolated a new mutant, nalyot (nal). Molecular characterisation revealed that the nalyot mutation

536

Paper alert

was in a previously identified gene, Adf1, an essential Drosophila sequence-specific transactivator that binds the promoters of a diverse group of genes. Mild hypomorphic Adf1 mutants (née nalyot) exhibit a moduated initial learning disruption with subsequent normal short-term memory decay. However, these mutants are defective in long-term memory. The learning and memory deficits observed in Adf1 mutants do not result from abnormalities in their abilities to sense, or react to, the odours or electroshock used during conditioning. Although ADF1 has a broad level of expression in the developing central nervous system (CNS), the authors did not detect any disruptions in gross morphology of the CNS in these hypomorphic Adf1 mutants. However, when they examined the larval neuromuscular junction, Adf1 appeared to have a role in the modulation of synaptic growth. An inherited functional circadian clock in zebrafish embryos. Delauney F, Thisse C, Marchand O, Laudet V, Thisse B: Science 2000, 289:297-300. • Significance: Oscillations in the mRNA levels of a clock gene are observed in the nervous system of the zebrafish embryo. These mRNA cycles are observed at the earliest stages after fertilisation, as well as in unfertilised oocytes, and reveal for the first time the maternal inheritance of circadian cycles of gene expression. Findings: The authors isolated the mammalian mPer3 homologue in the zebrafish and examined its expression in embryos. The central nervous system and retina showed robust cycles of mRNA expression from days 2–6 post-fertilisation in 24h light–dark (LD) schedules. Altering the LD regime reset the rhythm, and the cycle was maintained in constant light or darkness, thereby revealing its endogenous nature. Further experiments showed that the cycle was independent of the timing of fertilisation. In fact, unfertilised oocytes have a rhythm with the same phase as very young embryos, suggesting that the latter synchronise their cycle by using maternal gene products. This provides an adaptive response because the embryo would inherit the same phase as its mother, even though there is no direct communication between them.

such that the steady state inactivation curve was shifted approximately –10 mV by 10–100 µM synthetic peptide. Familial Parkinson disease product, parkin, is a ubiquitinprotein ligase. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T: Nat Genet 2000, 25:302-305. • Significance: Assigns a biochemical function to the protein Parkin, which causes autosomal recessive juvenile parkinsonism (AR-JP) when mutated. Several neurodegenerative disorders are now known to either include or be caused by defects in the ubiquitination-proteosome system. Findings: Parkin is shown to represent an E3 class (ubiquitinligating) enzyme by virtue of its co-immunoprecipitation with the E2 (ubiquitin-conjugating) enzyme UbcH7 and its ability to ubiquitinate substrates given the appropriate conditions in vivo and in vitro. Parkin mutants found in AR-JP were defective in either E2 interaction or substrate ubiquitination directly. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W et al.: Nat Med 2000, 6:797-801. • Significance: Previous studies suggested that caspase-1 is activated in the brains of Huntington’s disease (HD) patients and in a mouse model of HD (R6/2), and genetic or pharmacological inhibition of caspase-1 was shown to reduce disease symptoms and delay mortality in R6/2 mice. Here it is shown that an FDA-approved orally available drug, minocycline, also has these same beneficial effects in R6/2 mice. This drug may become clinically useful for the treatment of HD. Findings: R6/2 mice develop higher levels of caspase-1 and caspase-3 than control mice and this increase was blocked by minocycline treatment. HD patients and R6/2 mice have higher levels of inducible nitric oxide synthetase (iNOS) activity than normal, and in R6/2 mice this is also blocked by minocycline. Although the mechanism of action of the minocycline remains unclear, it significantly improved rotarod performance and extended lifespan in R6/2 mice.

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

An endogenous pentapeptide acting as a sodium channel blocker in inflammatory autoimmune disorders of the central nervous system. Brinkmeier H, Aulkemeyer P, Wollinsky KH, Rudel R: Nat Med 2000, 6:808-811. • Significance: It has been hypothesized that endogenous sodium channel blockers (‘endocaines’) exist and that the rapid relapses observed in demyelinating autoimmune disorders might be related to fluctuations in these factors. These investigators isolated a five-amino-acid peptide that reversibly inhibits sodium channel currents similarly to lidocaine and which is increased up to ten-fold in cerebrospinal fluid (CSF) from multiple sclerosis (MS) and Guillain-Barre syndrome (GBS) patients. This discovery opens up new possiblities for understanding and treating these diseases. Findings: A sodium-channel-blocking activity that was present in MS and GBS CSF was purified and isolated by a series of chromatographic methods, sequenced by mass spectometry, and found to be Glu-Tyr-Asn-Ala-Asp (QYNAD). Both the purified CSF factor and synthetic QYNAD altered the voltage dependence of inactivation of sodium channels in a neuroblastoma-glioma cell line

Identification of receptors for neuromedin U and its role in feeding. Howard AD, Wang R, Pong S-S, Mellin TN, Strack A, Guan X-M, Zeng Z, Williams DL Jr, Feighner SD, Nunes CN et al.: Nature 2000, 406:70-74. •• Significance: Neuromedin U (NMU) is a neuropeptide known to affect smooth muscle function. In this report, two receptors for NMU are identified, and the finding that NMU can act in the brain to affect appetitive behavior is first described. Findings: To identify their ligand(s), cells expressing the orphan G-protein coupled receptor FM-3, or its homologue FM-4, the cloning of which is described in this report, were screened with a panel of known peptides and were found to respond robustly to NMU. FM-3 and FM-4 were renamed NMU1R and NMU2R, respectively. In situ hybridization and Northern blot revealed expression of NMU1R in several tissues including the goblet cells of the small intestine. NMU2R is expressed in specific regions of the brain including the paraventricular nucleus of the hypothalamus, the ependyma of the third ventricle, and the CA1 region of the hippocampus. NMU is expressed in the feedingrelated arcuate nucleus of the hypothalamus, and is down-regulated in response to fasting. NMU peptide administered intracerebroventricularly reduced feeding behavior in rats.

Paper alert

A one-hit model of cell death in inherited neuronal degenerations. Clarke G, Collins RA, Leavitt BR, Andrews DF, Hayden MR, Lumsden CJ, McInnes RR: Nature 2000, 406:195-199. • Significance: This study uses mathematical modeling to provide evidence that cell death in neurodegenerative disorders is probably not a result of cumulative damage within susceptible cells as has been proposed, but instead is likely to result from an altered steady state in which a single event initiates cell death. Findings: These investigators reasoned that cumulative damage or increasing risk to cells would produce a sigmoidal curve of cell-death kinetics, whereas a constant or decreasing risk would yield an exponential curve. From several sources they collected data on many neurodegenerative conditions including 12 models of photoreceptor degeneration, hippocampal excitotoxicity, cerebellar degeneration in pcd mice, Parkinson’s disease, 6-OHDA (6-hydroxydopamine) treated rats, and Huntington’s disease. In each case the data indicated that the kinetics of cell death were exponential, implying a constant or decreasing risk for each neuron. Selected by Gerd Kempermann and Juergen Winkler Department of Neurology, University of Regensburg, Regensburg, Germany

Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Casoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A: Proc Natl Acad Sci USA 2000, 97:6826-6831. • Significance: One of the major scientific problems for the study of Alzheimer’s disease is that no good animal model exists that mimicks the pathology found in the adult brain. This article is the first to describe a new animal model for severe neurodegenerative disease. Findings: Aged mice expressing a neutralizing antibody against nerve growth factor (NGF) developed a phenotype indicating progressive neurodegeneration. The pathological features included amyloid plaques, hyperphosphorylated Tau protein, neurofibrillary tangles, neuronal cell loss, cholinergic deficits and behavioral disturbances. The study shows that loss of NGF function results in neurodegeneration. Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion. Labuda M, Labuda D, Miranda C, Poirier J, Soong B, Barucha NE, Pandolfo M: Neurology 2000, 54:2322-2324. • Significance: This article describes an important detail regarding the inheritance of Friedreich ataxia and puts forward the interesting evolutionary aspect of why Friedreich ataxia is found only in Europeans, North Americans, Middle Easterns and Indians. Findings: On the basis of linkage analysis of normal alleles to the disease-causing triplet GAA repeat expansions, this study shows a common origin of all chromosomes containing more than 12 GAA repeats. Expansions of GAA triplet repeats arose through a unique two-step process presumably in Africa. One or few of these chromosomes subsequently migrated to Europe or to the Middle East, but not to China, Japan, or Southeast Asia. Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson’s disease. Brundin P, Pogarell O, Hagell P, Piccini P, Widner H, Schrag A, Kupsch A, Crabb L, Odin P, Gustavii B et al.: Brain 2000, 123:1380-1390.

537

•• Significance: Current clinical approaches for neural transplantation in the treatment of Parkinson’s disease (PD) rely on the use of human embryonic mesencephalic tissue. Relatively large amounts of human embryonic mesencephalic tissue need to be grafted because survival of transplanted dopaminergic neurons is very low (3–20% survival rate). Here, a promising strategy to improve graft survival has been applied in patients. Findings: Studies using animal models have shown that the lipid peroxidation inhibitor tirilazad mesylate improves the survival of transplanted cells and thus helps to reduce the amount of tissue that has to be transplanted. The authors show that in five PD patients a reduction in graft size by approximately 50% was possible, achieving similar functional outcome to that seen in earlier patients. Long-term follow-up of unilateral pallidotomy in advanced Parkinson’s disease. Fine J, Duff J, Chen R, Hutchison W, Lozano AM, Lang AE: N Engl J Med 2000, 342:1708-1714. • Significance: Surgical treatment such as unilateral pallidotomy has to be considered as adjunctive therapy for advanced Parkinson’s disease as a result of limited efficacy of levodopa therapy. This study shows that selected patients may have a long-term benefit from this surgical procedure. Findings: During long-term follow-up (mean time 52 months) of Parkinson patients (n = 20) with posteroventral medial pallidotomy, significant improvements were sustained in ‘off-period’ (i.e. overnight withdrawal of medication) contralateral signs of Parkinsonism such as bradykinesia, tremor and rigidity, and also in ‘on-period’ (i.e. daytime with medication) contralateral dyskinesia, but not in other ‘on-period’ signs of Parkinsonism. These improvements worsened during the follow-up, but were still significantly different at the final assessment in comparison with baseline results. Physical activity and risk of stroke in women. Hu FB, Stampfer MJ, Colditz GA, Ascherio A, Rexrode KM, Willett WC, Manson JAE: JAMA 2000, 283:2961-2967. • Significance: Increasing physical activity levels such as moderate-intensity exercise (e.g. walking) is associated with a significant reduction in risk of total and ischemic stroke in a dose-dependent manner. This large prospective cohort study shows that regular physical exercise prevents chronic neurological disease. Findings: During 8 years follow-up, the risk of total stroke and ischemic stroke was significantly lower in female nurses (n = 72488) with increased walking activity (walking hours >0.6–2.0 hr/wk) and intensity (walking speed >2–2.9 mph). Sedentary women who change walking habits in mid- or lateadulthood (3.5 hr/wk increase) have a 19% or 29% reduction in total or ischemic stroke, respectively. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Nadin A, Neduvelll JG, Register RB et al.: Nature 2000, 405:689-694. AND

Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, Wolfe MS: Nat Cell Biol 2000, 2:428-434. AND

Total inactivation of γ-secretase activity in presenilindeficient embryonic stem cells. Herreman A, Serneels L,

538

Paper alert

Annaert W, Collen D, Schoojans L, De Strooper B: Nat Cell Biol 2000, 2:461-462. AND

Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA: Nat Cell Biol 2000, 2:463-465. • Significance: Cleavage of the amyloid precursor protein (APP) by γ-secretase plays a major role in the amyloidogenic pathogenesis of Alzheimer’s disease (AD). These studies add substantial evidence that the presenilins function as γ-secretases. The development of inhibitors of γ-secretase

activity may lead to a new strategy for the treatment and prevention of AD. Findings: Presenilin-1 (PS1) and presenilin-2 (PS2) mutations are associated with early-onset familial AD leading to an increased accumulation of the amyloid β-protein (42-amino-acid form of Aβ) generated from the larger APP. To investigate APP metabolism, Herreman et al. and Zhang et al. show that γ-secretase activity is completely eliminated in presenilin-deficient embryonic stem cells. Esler et al. and Li et al. use potent transition-state analogue inhibitors of γ-secretase which are directed to the aspartyl protease site of the presenilins, and are able to block the generation of Aβ in a dose-dependent manner.