Neurobiology

Neurobiology

347 Neurobiology Paper alert A selection of interesting papers that were published in the two months before our press date in major journals most lik...

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347

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. • ••

of special interest of outstanding interest

Current Opinion in Neurobiology 2001, 11:347–353 Contents (chosen by) 347 Development (Price) 347 Cognitive neuroscience (Silva, Kushner and Reber) 348 Signalling mechanisms (Häusser and Mittmann) 349 Sensory systems (Wood) 350 Neuronal and glial cell biology (Bredt) 350 Motor systems (Chafee and Merchant) 351 Neurobiology of behaviour (Goodwin and Kyriacou) 352

Neurobiology of disease (Kempermann and Winkler)

Development Selected by Jack Price Institute of Psychiatry, London, UK e-mail: [email protected]

• Adaptation in the chemotactic guidance of nerve growth cones. Ming G-I, Wong ST, Henley J, Yuan X-B, Song H-J, Spitzer NC, Poo M-M: Nature 2002, 417:417-8418 Significance: A mechanistic analysis of adaptation in the chemotactic guidance of growth cones. Findings: We have recognised for some time that growth cone guidance can be mediated by gradients of extracellular guidance factors. However, for such chemotaxis to work, the growth cone must be sensitive to small gradients of factors across a considerable concentration range. This suggests that the growth cone must be able both to amplify the signal and to readjust its sensitivity to the factor. The authors of this study demonstrate a mechanism whereby this is achieved. They show that the growth cones of Xenopus spinal neurons are capable of desensitisation and resensitisation to netrin-1 and brainderived neurotrophic factor, which are both chemotactic factors for these cells. They further show that Ca2+ signaling is lost in both cases, whereas resensitisation requires mitogen-activated protein kinase activation. Finally, they demonstrate that protein translation, but not mRNA synthesis, is required for both processes. There emerges from this study a clear model of how chemotactic guidance might be controlled in the growth cone. • Retinoic acid signaling in the zebrafish embryo in necessary during pre-segmentation stages to pattern the anterior–posterior axis of the CNS and to induce a pectoral fin bud. Grandel H, Lun K, Rauch G-J, Rhinn M, Piotrowski T, Houart C, Sordino P, Küchler AM, Schulte-Merker S, Giesler R et al.: Development 2002, 129:2851-2865 Significance: A novel role for retinoic acid during early neural patterning.

Findings: The role of retinoic acid during embryogenesis is well studied and much is known concerning its role during the somite stages of embryogenesis. This study identifies an earlier function of retinoic acid on neural tube patterning in the zebrafish. The authors show that a retinoic acid signal derived from the blastoderm margin and the involuting paraxial mesoderm is required for the proper expression of the spinal cord markers hoxb5a and hoxb6b. This suggests a role for retinoic acid in anteroposterior patterning. Support for this idea comes from the expression pattern for the gene no-fin, mutants of which fail to develop pectoral fins and posterior branchial arches, and which have a neural tube phenotype consistent with the attenuation of a posteriorising signal. This gene turns out to encode retinaldehyde dehydrogenase2 (raldh2), a retinoic acid synthetic enzyme; exogenous retinoic acid rescues the no-fin phenotype. This paper constitutes an interesting step forward in our understanding of early neural patterning. •• Control of neuronal subtype identity by the C. elegans ARID protein CFI-1. Shaham S, Bargmann CI, Genes Dev 2002, 16:972-983. Significance: An elegant study describing the identification and role of a novel DNA-binding protein in the determination of neuronal fate in the nematode. Findings: The four nematode CEM neurons are male-specific head neurons, with a putative chemosensory function. They are related to the URA and IL2 neurons, but their fate differs from that of URA and IL2 neurons in a number of aspects. How is this fate determined during development? Here, the authors conduct a genetic screen to identify novel genes involved in CEM neuronal fate. They identify two original mutations that allow them to identify a novel CFI-1 gene, which turns out to encode a DNA-binding protein of the ARID type, probably the orthologue of the Drosophila Dead ringer protein. Their experiments indicate that CFI-1 is important in generating neuronal diversity, by regulating expression of downstream genes. Specifically, differences between CEM neurons and the URA and IL2 cells are dictated by cfi-1 in conjunction with the POU domain gene unc-86. This is a clear exposition of how transcription factors can dictate fate in the developing nervous system.

Cognitive neuroscience Selected by Alcino J Silva and Steven A Kushner University of California-Los Angeles, California, USA e-mail: [email protected]

• Operant reward learning in Aplysia: neuronal correlates and mechanisms. Brembs B, Lorenzetti FD, Reyes FD, Baxter D, Byrne JH: Science 2002, 296:1706-1709. Significance: Proposal of a cellular mechanism for plasticity of an appetitive operant conditioning procedure in Aplysia. Findings: Brembs et al. examine in vivo operant learning using the consummatory phase of feeding, an easily quantified all-ornothing behavior with well-characterized neuronal circuitry. During food ingestion, they reliably observed bouts of

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high-frequency activity in the anterior branch of the esophageal nerve (EN), using chronically implanted extracellular electrodes in Aplysia. In contrast, EN activity recorded during spontaneous biting in the absence of food was minimally increased. The authors reason that EN activity might substitute for food reinforcement during spontaneous biting. Indeed, contingent stimulation of the EN during spontaneous biting resulted in a significant increase in spontaneous bite rate. Given that activity in the buccal central pattern generator network underlies movements during feeding behavior, Brembs et al. conducted intracellular recordings from an identified buccal neuron, B51, important for the production of ingestion-like buccal motor patterns (BMP). Direct depolarization of B51 resulted in BMP activity, whereas hyperpolarization inhibited such activity. Consistent with the hypothesis that B51 may be a locus of plasticity for operant feeding behavior, a significant decrease in the burst threshold and increase in the input resistance were observed in animals receiving contingent training but not unpaired conditioning. The authors also modeled reinforcement in isolated B51 neurons using an iontophoretic puff of dopamine and a brief suprathreshold depolarizing current pulse was used to simulate spontaneous biting. Seven trials over 10 minutes of contingent application of dopamine immediately following suprathreshold current injections resulted in a significant decrease in burst threshold and increase in input resistance, similar to the effects observed in vivo. • Reversible inhibition of CREB-ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Pittenger C, Huang YY, Paletzki RF, Bourtchouladze R, Scanlin H, Vronskaya S, Kandel ER: Neuron 2002, 34:447-462. Significance: The first demonstration of the selective necessity of CREB function in the CA1 region of the dorsal hippocampus for spatial learning. Findings: Here, the authors utilized a transgenic line of mice (dCA1-KCREB) expressing a dominant-negative point mutation at Lys304 in CREB. KCREB is known to be a potent repressor of CREB-mediated transcriptional activation. In one of the lines obtained, transgene expression was selectively localized to CA1 cells of the dorsal hippocampus. A battery of neurologic tests did not detect any abnormalities in dCA1-KCREB mice; however, tests in the Morris water maze revealed spatial learning and memory deficits. Interestingly, mice expressing the mutant CREB transgene selectively in the striatum showed normal spatial learning. Using object recognition tests, the authors show that although short-term memory was intact, long-term recognition memory was almost completely eliminated in mice expressing the dCA1-KCREB transgene. The phenotype in the dCA1-KCREB mice was not due to a developmental problem because repression of transgene expression restored the ability of dCA1-KCREB mice to perform normally in both the water maze and object recognition. Interestingly, synaptic potentiation at the Schaffer collateral synapse in dorsal hippocampal slices in response to forskolin was significantly reduced in transgenic animals, a result consistent with a role for CREB downstream of cAMP signaling. Potentiation was also impaired with application of a dopamine D1 agonist. Selected by Paul J Reber Northwestern University, Evanston, Illinois, USA e-mail: [email protected]

Neglect disrupts the mental number line. Zorzi M, Priftis K, Umilta C: Nature 2002, 417:138-139.

Significance: Left neglect from a right parietal lesion affects internal representation of number relationships in a manner similar to viewing a mental number line. Findings: Patients with persistent left-neglect were tested on an interval bisection test in which they were asked to identify the midpoint of a pair of numbers (e.g. 11–19). They were found to consistently err towards choosing a number near the upper end of the interval. This behavior is consistent with visual line bisection in neglect patients and appears to reflect neglect of the left side of the ‘number line’ representation of the numerical interval. The patients otherwise demonstrated intact numerical and arithmetic skills. This result suggests that the popular metaphor of a ‘mental number line’ in fact describes an internal representation that is spatially isomorphic to an imagined visual line. Critical role of the hippocampus in memory for sequences of events. Fortin NJ, Agster KL, Eichenbaum HB: Nat Neurosci 2002, 5:458-462. Significance: Hippocampal lesions disrupt memory for the sequential order of a series of odors, even though recognition of previously seen stimuli remains intact. Findings: Rats with hippocampal lesions were found to be impaired on a memory test of sequential order of a series of odors. Control animals were able to select the odor matching the one that preceded a probe stimulus, but lesioned animals performed near chance. Recognition of odors presented within the sequence was intact following hippocampus lesions indicating that the hippocampus plays a selective, critical role in storage of a series of events, as would be expected in the storage of episodic memory traces. Cognitive slowing in Parkinson’s disease: a behavioral evaluation independent of motor slowing. Sawamoto N, Honda M, Hanakawa T, Fukuyama H, Shibasaki H: J Neurosci 2002, 22:5198-5203. Significance: Patients with Parkinson’s disease show general slowing in effecting mental operations, indicating that striatal dysfunction is associated with cognitive as well as motor impairments. Findings: Depletion of dopamine in the basal ganglia in Parkinson’s disease (PD) is known to impair motor control for these patients and has been suggested to affect specific cognitive functions. A test of processing speed for verbal and spatial stimuli found that PD patients were significantly slowed in general cognitive processing, leading to increased error rates on fast-paced tasks. The processing test was constructed to eliminate demands on response speed in order to create a direct test of the sustainable speed of sequential cognitive operations. The impairment of the PD patients on this test raises the possibility that a general impairment in cognitive processing speed may play a role in reports of cognitive dysfunction in PD.

Signalling mechanisms Selected by Michael Häusser and Wolfgang Mittmann University College London, London, UK e-mail: [email protected]

•• Single and multiple vesicle fusion induce different rates of endocytosis at a central synapse. Sun JY, Wu XS, Wu LG: Nature 2002, 417:555-559.

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•• Capacitance steps and fusion pores of small and large-dense-core vesicles in nerve terminals. Klyachko VA, Jackson MB: Nature 2002, 418:89-92. Significance: The first direct measurements of capacitance changes associated with the release and subsequent endocytosis of single vesicles at mammalian synaptic terminals. Findings: These papers represent stunning technical breakthroughs using complementary methods. Sun et al. made simultaneous measurements of presynaptic capacitance and postsynaptic excitatory postsynaptic currents (EPSCs) at the brainstem calyx synapse, and used averaging techniques to isolate the mean capacitance change associated with release of a single quantum of transmitter and the subsequent endocytosis. The mean singlequantum capacitance change (65 aF) is consistent with measured vesicle diameters and confirms that single quanta result (on average) from the release of a single vesicle. The authors also show directly that enhancing exocytosis inhibits the rate of endocytosis in a calcium-independent manner. Klyachko and Jackson complement and extend the Sun et al. study by improving the signal-to-noise ratio sufficiently to record single-vesicle capacitance steps at pituitary nerve terminals using cell-attached recording. The authors observed capacitance steps corresponding to release of both large dense-core vesicles as well as microvesicles, and demonstrate that both types of vesicle undergo ‘kiss-and-run’ reversible fusion events associated with fusion pores of different sizes. • A single packet of transmitter does not saturate postsynaptic glutamate receptors. Ishikawa T, Sahara Y, Takahashi T: Neuron 2002, 34:613-621. Significance: Direct evidence that glutamate released from single presynaptic vesicles does not saturate postsynaptic glutamate receptors. Findings: The authors used patch-clamp recording from the giant calyx of Held presynaptic terminal to load the terminal with high concentrations of the transmitter L-glutamate in order to increase vesicular glutamate concentration. This potentiated both evoked and quantal EPSCs mediated by AMPA and NMDA glutamate receptors, demonstrating that the amount of glutamate normally present in a single vesicle does not saturate these receptors. • A monomeric red fluorescent protein. Campbell RE, Tour O, Palmer AE, Steinbach PA, Baird GS, Zacharias DA, Tsien RY: Proc Natl Acad Sci USA 2002, 99:7877-7882. Significance: The use of DsRed opens the door to multicolour labelling for tracking protein expression and localisation, and may lead to improved fluorescence resonance energy transfer sensors. Findings: Monomeric red fluorescent protein provides a spectrally distinct alternative to the widely used green fluorescent protein. The red fluorescent protein from Discosoma coral (DsRed) matures slowly and forms obligate tetramers, which has precluded its use as a genetically encoded fusion label. The authors disrupted the dimerization interface of DsRed using targeted mutagenesis, which generated a monomeric weakly fluorescent protein. They then used random and directed mutagenesis to isolate a highly fluorescent and rapidly maturing variant, capable of forming fully functional fusion proteins. • Nonlinear signal transfer from mouse rods to bipolar cells and implications for visual sensitivity. Field GD, Rieke F: Neuron 2002, 34:773-785. Significance: A demonstration of how nonlinear signalling between rods and bipolar cells optimises the signal-to-noise ratio at visual threshold.

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Findings: Rods in the mammalian retina pay the price for their high sensitivity with strongly overlapping distributions of signal and noise. At light intensities close to threshold, voltageclamped rods show linear light responses, whereas rod-bipolar cells show supralinear responses. Therefore, bipolar cells penalise small responses, rejecting noise and also a large fraction of small single photon responses, whereas larger responses are rewarded with a supralinear current. This nonlinearity is suggested to occur before pooling of the 10–20 rod inputs and separates the distributions of signal and noise, improving the signal-to-noise ratio several hundred times. •• Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Hardingham GE, Fukunaga Y, Bading H: Nat Neurosci 2002, 5:405-414. Significance: Reveals that the same neurotransmitter receptor can have opposite effects on gene regulation and cell survival depending on whether it is located at the synapse or extrasynaptically. Findings: The authors investigated the response of cultured pyramidal neurons to activation of synaptic and extrasynaptic NMDA receptors by glutamate. Synaptic activation of NMDA receptors triggered calcium influx, which induced CREB activity, and brain-derived neurotrophic factor (BDNF) gene expression, thus promoting neuronal survival. In contrast, activation of extrasynaptic NMDA receptors by bath application of glutamate or hypoxic/ischemic conditions produced opposite effects on CREB activity and BDNF expression, leading to cell death. Selective block of synaptic and extrasynaptic receptors may thus provide a novel target for therapeutic drugs.

Sensory systems Selected by John N Wood University College London, London, UK e-mail: [email protected]

•• Characterization of an orphan G-protein-coupled receptor localized in the dorsal root ganglia reveals adenine as a signaling molecule. Bender E, Buist A, Jurzak M, Langlois X, Baggerman G, Verhasselt P, Ercken M, Guo HQ, Wintmolders C, Van Den Wyngaert I et al.: Proc Natl Acad Sci USA 2002, 99:8573-8578. Significance: Identification of the first receptor for adenine as a dorsal root ganglion-selective orphan G-protein-coupled receptor. Findings: By degenerate PCR, the authors cloned a previously unknown G-protein-coupled receptor (GPCR). mRNA expression profiling indicated highest expression of this GPCR in the subset of small dorsal root ganglion neurons involved in damage detection. Some expression was also found in lung, hypothalamus, peripheral blood leukocytes, and ovaries. Using a functional assay and tissue fractionation, adenine was found to activate the receptor with high structural stringency at nanomolar concentrations. This receptor has thus been defined as an adenine receptor. This is the first demonstration of adenine as a signaling molecule in mammals and adds a third family besides P1 and P2 receptors to the class of purinergic receptors. In addition, this work suggests that adenine may have a previously unsuspected role in nociception and pain. •• TRPV3 is a calcium-permeable temperature-sensitive cation channel. Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, Ge P, Lilly J, Silos-Santiago I, Xie Y et al.: Nature 2002, doi:10.1038/nature00882.

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•• TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, Wright JE, Jerman JC, Walhin JP, Ooi L et al.: Nature. 2002, [doi:10.1038/nature00894. •• A heat-sensitive TRP channel expressed in keratinocytes. Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P et al.: Science 2002, 296:2046-2049. Significance: A new mammalian heat sensor that is not activated by hot chilli peppers! Findings: Transient receptor potential (TRP) channels are involved in extracellular signal detection in worms, flies and mice. These three papers focus on a close relative of the capsaicin receptor TRPV1, previously known as vanilloid receptor-1 (VR-1). TRPV1 is a cation-selective ion channel that is gated by noxious heat, low pH, as well as the hot pepper ingredient capsaicin. The new channel, named TRPV3, is structurally similar to VR1 and is located at an adjacent site on the chromosome. However, TRPV3 is capsaicin-insensitive and activated at lower temperatures (38°C) than TRPV1. This may explain why TRPV1-null mutant mice show apparently normal heat responses. TRPV3 seems to be able to heteromultimerise with TRPV1 to give a channel with novel properties. In addition, TRPV1 is found in non-neuronal cells such as keratinocytes, where its activation may result in the release of chemical mediators that act on sensory neurons. TRPV3 adds yet another member to the TRP receptor class that seems to be important in many aspects of extracellular signal transduction (light, mechanical, thermal and chemical) throughout the animal kingdom.

between postsynaptic EphB receptors and presynaptic B-ephrins play a role in this induction. Findings: Using hippocampal slices, the authors find that profusion of postsynaptic neurons, with peptides or antibodies that block binding of EphB receptor tyrosine kinases to the PDZ protein GRIP, prevents induction of mossy fiber LTP. This LTP was also blunted by the extracellular application of soluble forms of B-ephrins, which are the presynaptic ligands for EphB receptors. This study thus identifies a retrograde signaling pathway through which EphB receptor–ephrinB ligand interactions link postsynaptic induction with presynaptic expression of long-term changes in glutamate release. • PSD-95 mediates formation of a functional homomeric Kir5.1 channel in the brain. Tanemoto M, Fujita A, Higashi K, Kurachi Y: Neuron 2002, 34:387-397. Significance: A demonstration that channel activity is induced when Kir5.1 is coexpressed with the postsynaptic density protein, PSD95. Findings: Inwardly rectifying K+ channels (Kir) play critical roles in controlling the excitability of neurons and other cells. The Kir5.1 subunit is highly expressed in brain but does not form an independent functional channel. Using transfection into a heterologous cell line, the authors find that Kir5.1 channel activity is detected when coexpressed with PSD95. This is mediated by PSD95 enhancing the surface expression of Kir5.1, which is otherwise rapidly internalized. This Kir5.1/ PSD-95 channel complex is also regulated by protein kinase (PKA), as channel activity is promptly suppressed by PKA activation. These studies identify a functional channel property for Kir5.1 and define a new property for PSD95 as an essential channel subunit.

•• Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin cell. Mukouyama Y, Shin D, Britsch S, Taniguchi M, Anderson DJ: Cell 2002, 109:693-705. Significance: Peripheral sensory nerves determine the pattern of development of arteries but not veins, through the release of soluble growth factors. Findings: Arteries, but not veins are shown here to align with peripheral nerves in embryonic mouse limb skin. Normal arterogenesis requires sensory nerves and Schwann cells, whereas mutants with disorganised peripheral nerves still align arteries along the misrouted axons. In vitro, both sensory neurons or Schwann cells induce arterial marker expression in embryonic endothelial cells, via the secretion of vascular endothelial growth factor VEGF164/120, which is both necessary and sufficient to mediate the induction. Thus, peripheral nerves seem to determine the pattern of arterial branching and arterial differentiation in the skin, via local secretion of VEGF.

• RNA editing at Arg607 controls AMPA receptor exit from the endoplasmic reticulum. Greger IH, Khatri L, Ziff EB: Neuron 2002, 34:759-772. Significance: Description of an unexpected role for Arg607 in controlling AMPA receptor exit from the endoplasmic reticulum. Findings: This study demonstrates that a large fraction of the AMPA receptor GluR2 subunit resides stably in an intracellular pool in the endoplasmic reticulum (ER), where it is complexed with GluR3. Exit from the ER requires both interactions with the PDZ motif at the C-terminus of GluR2 and Q/R-editing of Arg607. This mechanism for retention of GluR2 subunits allows the neuron to presumably control the number of functional receptors at the plasma membrane. Because changes in the number of synaptic AMPA receptors play a critical role in synaptic plasticity, this work has important implications for control of activity-dependent synaptic strength.

Neuronal and glial cell biology

Motor systems

Selected by David S Bredt University of California at San Francisco, San Francisco, California e-mail: [email protected]

Selected by Matthew Chafee* and Hugo Merchant Brain Sciences Center, VAMC, Minneapolis, Minnesota, USA *e-mail: [email protected]

• Trans-synaptic Eph receptor–ephrin signaling in hippocampal mossy fiber LTP. Contractor A, Rogers C, Maron C, Henkemeyer M, Swanson GT, Heinemann SF: Science 2002, 296:1864-1869. Significance: Suggestion that a postsynaptic locus may be responsible for induction of long-term potentiation (LTP) at mossy fiber–CA3 synapses and that transsynaptic interactions

•• Direct cortical control of 3D neuroprosthetic devices. Taylor DM, Tillery SIH, Schwartz AB: Science 2002, 296:1829-1832. Significance: The accuracy of brain-controlled virtual movements improves as the neurons controlling the process improve their directional tuning. Findings: Monkeys made reaching movements towards eight spherical targets in a 3D virtual workspace. Visual feedback

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regarding movement was provided by a spherical cursor. The cursor could be alternately placed under ‘hand-control’ (cursor coupled to wrist position) or ‘brain-control’ (cursor coupled to the population vector decoded from simultaneously recorded neurons in primary motor cortex). When under brain-control, both arms were restrained, and the monkey moved the cursor to the target using the activity of neurons in motor cortex only. Cursor trajectories were compared under open-loop and closed-loop conditions. In the open-loop condition, trajectories were reconstructed offline from the activity of the neurons on hand-control trials after the trials were performed (the monkey did not view the control of the cursor by neural activity in this case). In the closedloop condition, the trajectory of the cursor was controlled directly by neural activity, and the monkey had visual feedback as to the accuracy of this control. Cursor trajectories were more accurate under closed-loop than open-loop conditions. This indicated that the visual feedback regarding the neural to cursor coupling modified neural activity in motor cortex such that direct neural control improved. The improvement in accuracy was reflected in an improvement in the directional tuning of the cells. The important implication is that it is only necessary to record the activity of a small number of randomly encountered motor cortical neurons as these neurons can adapt to visuomotor tasks with practice. Neural control of the cursor was also achieved using an algorithm that iteratively optimized directional parameters controlling the brain to cursor relation. This did not require prior knowledge of the preferred directions of the neurons derived from trials in which actual reaching movements were made, which would be impossible to achieve in the case of a prosthetic device replacing a lost limb. • Cerebellum activation associated with performance change but not motor learning. Seidler RD, Purushotham A, Kim SG, Ugurbil K, Willingham D, Ashe J: Science 2002, 296:2043-2046. Significance: Functional activation of the cerebellum in an implicit motor learning paradigm is related to improved performance, but not to motor learning. Findings: Motor learning and improved performance are normally correlated; however, this study dissociates these two components. Human subjects depressed four buttons in response to the sequential illumination of four square visual stimuli either at random, or in a repeating 12-stimulus sequence. Implicit learning in the case of repeating sequences of movements is evident as a reduction in mean reaction time and error rate without explicit awareness of the underlying sequence. During the encoding phase of the experiment, subjects concurrently depressed buttons in response to the sequential stimuli and performed a distractor task. The distractor task blocked improved motor performance during the encoding phase, but did not prevent motor learning. In the subsequent expression phase of the experiment (without the distractor task), subjects responded with greater speed and accuracy to the previously repeated sequence. The functional activation of the cerebellum was assessed in the encoding phase, when implicit motor learning took place, and the expression phase, when this learning was expressed in improved reaction time and accuracy. No activation was evident in the encoding phase. Cerebellar activation was evident in the expression phase, and correlated with measures of improved motor performance. • A pathway in primate brain for internal monitoring of movements. Sommer MA, Wurtz RH: Science 2002, 296:1480-1482.

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Significance: Physiological identification of an anatomical pathway in the primate that is competent to carry corollary discharge signals from downstream to upstream regions. Inactivation of this pathway produces errors attributable to the degraded neural representation of prior movements. Findings: Neurons in the superior colliculus project both downstream to oculomotor neurons in the brainstem and upstream to relay neurons in the mediodorsal (MD) thalamus. MD relay neurons then project to the frontal eye fields. This arrangement places the MD nucleus midway in a pathway that could relay corollary discharge of motor commands initially generated in the superior colliculus upstream to the frontal eye fields. To test this, antidromic and orthodromic stimulation was used to identify single MD neurons that received projections from the superior colliculus and that projected to the frontal eye fields. These neurons were predominately activated prior to saccadic eye movements, consistent with their carrying a corollary discharge of oculomotor commands. Inactivation of this region of the MD nucleus produced a subtle but consistent shift in the endpoint of the second saccade in a double saccade task. The shift was in a direction predicted by a failure to fully compensate for the first saccade, the accuracy of which was not affected. The results provide evidence that some signals coursing through the MD nucleus represent corollary discharge of oculomotor commands, and that without these signals, the brain is less able to accurately represent saccadic eye movements it has previously commanded.

Neurobiology of behaviour Selected by Stephen Goodwin* and Bambos Kyriacou† *University of Glasgow, Glasgow, UK e-mail: [email protected] †University of Leicester, Leicester, UK e-mail: [email protected]

• Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Akhtar RA, Reddy AB, Maywood ES, Clayton JD, King VM, Smith AG, Gant TW, Hastings MH, Kyriacou CP: Curr Biol 2002, 12:540-550. • Coordinated transcription of key pathways in the mouse by the circadian clock. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB: Cell 2002, 109:307-320. • Extensive and divergent circadian gene expression in liver and heart. Storch KF, Lipan O, Leykin I, Viswanathan N, Davis FC, Wong WH, Weitz CJ: Nature 2002, 417:78-83. Significance: A comprehensive use of microarrays to assay circadian gene expression in at least two murine tissues, of which one, the liver, is represented in each paper. In the periphery, 5–9 % of the genes expressed in the liver cycle, but the identity of cycling genes is organ-specific. Findings: Panda et al. and Storch et al. used high-density oligonucleotide arrays, whereas Akhtar et al. screened a cDNA microarray to assay circadian rhythmicity. In spite of using different analytical methods and different experimental procedures to harvest the mRNA, the correspondence between the three studies is impressive, with approximately a 70% concordance between the three studies. All three studies found that 5–9% of expressed genes cycle in the liver; however, of these, only about 10% cycle in the suprachiasmatic nucleus (SCN; Panda et al.), or the heart (Storch et al.), or in the hypothalamus (Akhtar et al.).

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Thus, the overlap in the identity of cycling genes between organs is small, raising the issue that perhaps most genes may cycle in one tissue or another. Panda et al. revealed that in arrhythmic Clk/Clk mutant mice, only a minority of cycling genes in the liver altered their expression, suggesting that very few of these loci are under direct transcriptional control of core oscillator components. Akhtar et al. on the other hand, ablated the SCN, and found that in these behaviourally arrhythmic mice, the cycling of nearly all of the rhythmic genes in the liver was severely dampened. Thus, although the liver expresses all the core clock components that are required to generate molecular cycling, it requires a signal from the SCN to express these peripheral oscillations in gene expression (see Cheng et al. below). The genes that show circadian cycling represent a bewildering array of physiological processes, with coordinated expression of many genes within particular pathways, and with rate-limiting steps particularly well-represented within the cycling gene subsets. •• Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Cheng MY, Bullock CM, Li C, Lee AG, Bermack JC, Belluzzi J, Weaver DR, Leslie FM, Zhou Q-Y: Nature 2002 417:405-410. Significance: Identification of Prokineticin 2 (PK2) as a key output molecule in generating circadian locomotor behaviour in mice. Findings: The mechanism that generates intracellular circadian rhythmicity of clock molecules in the mammalian pacemaker, the SCN is well understood. This is in marked contrast to our knowledge of how SCN cells transmit their intracellular cycling signal to effector organs that generate rhythmic behaviour. PK2 is a cysteine-rich secreted protein that is expressed in smooth muscle of the gastrointestinal tract, and in discrete regions of the brain, including the SCN, where the transcript shows an abundance cycle in light:dark and total darkness conditions, with a peak during the (subjective) light phase. The PK2 promoter contains E-boxes and is responsive to the CLK-BMAL1 heterodimer that also activates cyclical transcription of mPER and mCRY clock genes, and is negatively regulated by mPER and mCRY. Mutations in these core clock genes thus have predictable effects on cycling PK2 expression in the SCN. Furthermore, light affects an upregulation of PK2 expression that correlates with the phase shifting effects of light on circadian behaviour. The PK2 receptors PKR1 and PKR2 are coexpressed with PK2 in most SCN neurons and in other brain regions known to be targets of SCN efferents, suggesting that PK2 is an output molecule for the SCN. In cell lines, PK2 expression activated PKR2 expression, which in turn mediated BMAL1-CLK activation of PK2, indicating a positive feedback loop dependent on clock proteins. Finally, direct brain injections of PK2 at night suppressed night-time locomotor activity, suggesting that the normal low levels of PK2 at night disinhibit wheel-running. PK2 therefore satisfies a number of criteria that are required to identify a circadian output molecule.

Neurobiology of disease Selected by Gerd Kempermann* and Juergen Winkler† *Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany e-mail: [email protected] †Department of Neurology, University of Regensburg, Germany e-mail: [email protected]

• Dopamine-dependent neurotoxicity of α-synuclein: A mechanism for selective neurodegeneration in Parkinson

disease. Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA: Nat Med 2002, 8:600-606. Significance: An important step towards a better understanding of why only dopaminergic neurons die in Parkinson disease. Findings: Xu et al. identified soluble protein complexes containing α-synuclein and protein 14-3-3 that mediate dopamine-dependent neurotoxicity in Parkinson’s disease. α-synuclein accumulation in cultured dopaminergic neurons caused cell death but not in non-dopaminergic cortical neurons. Thus, it appears that endogenous dopamine production is required for α-synuclein to exert its apoptosis-inducing effect. The study confirms the suspicion that dopamine itself might be involved in shifting the effect of α-synuclein from a neuroprotective factor to one related to cell death. The crucial next step will be to identify the mechanism by which this deadly interaction is triggered in Parkinson’s disease. • No major schizophrenia locus detected on chromosome 1q in a large multicenter sample. Levinson DF, Holmans PA, Laurent C, Riley B, Pulver AE, Gejman PV, Schwab SG, Williams NM, Owen MJ, Wildenauer DB et al.: Science 2002, 296:739-741. Significance: An important negative result indicates that the hunt for schizophrenia genes remains open. Findings: Earlier linkage studies had suggested a susceptibility locus for schizophrenia on chromosome Iq. To evaluate this potential linkage, the authors of this study genotyped markers on chromosome Iq in 779 pedigrees with a total of 1918 affected individuals. No significant linkage in this region could be detected. The authors conclude that genes in this region will have only small effects in patients outside the families in which the candidate regions were mapped. This study underlines how complex the genetics and the biology of schizophrenia remain and how careful the interpretation of data derived from small populations has to be. •• Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J et al.: Nat Med 2002, 8:500-508. Significance: Exemplary paper going beyond the mere analysis of gene array data from patient material by combining the approach with the validation of candidate pathways in an animal experiment. Findings: By comparing gene expression in acutely inflamed lesions with that in silent lesions from patients with multiple sclerosis, Lock et al. not surprisingly found regulation of numerous inflammatory cytokines. They then tested whether some of these genes could serve as a target for therapy in experimental autoimmune encephalitis. They found that, for example, knocking out granulocyte colony-stimulating factor, which is upregulated in acute lesions, leads to amelioration of the acute inflammatory condition. In contrast, the effect on the chronic state was greatest with the immunoglobulin Fc receptor common gamma chain. The study thereby shows that by a clever combination of gene array studies and animal experiments, hypotheses on new therapeutic strategies can be generated and validated. • Presenilin and nicastrin regulate each other and determine amyloid β-peptide production via complex formation. Edbauer D, Winkler E, Haass C, Steiner H: Proc Natl Acad Sci USA 2002, 13:8666-8671.

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Significance: Another important step in understanding the dynamic interplay of molecules in the orchestra of amyloid β-peptide deposition, one of the most important driving causes for the development of Alzheimer’s disease (AD). Findings: Amyloid β-peptide is generated by β-secretase cutting the N-terminus of the Aβ domain and γ-secretase cutting the C-terminus. Although β-secretase has been clearly identified as a membrane-bound aspartyl protease, evidence that the presenilin proteins, PS1 and PS2, act as γ-secretases, is still controversial. This study shows that PSs play an important role in the level of amyloid β-peptide production. It also provides evidence that the presence and binding of cofactors, such as nicastrin, to the PS complex may be required for the regulation of the complex biochemical pathway leading to amyloid β-peptide deposition in the central nervous system. • A polymorphic gene nested within an intron of the tau gene: implications for Alzheimer’s disease. Conrad C, Vianna C, Freeman M, Davies P: Proc Natl Acad Sci USA 2002, 99:7751-7756. Significance: Description of an interesting genetic risk factor for late onset AD and other tau-associated neurodegenerative disorders, facilitated by the Human Genome Project. Findings: Genetic studies of AD have identified several early onset-related risk factors, including mutations in the amyloid precursor protein, Presenilin 1, and Presenilin 2. The most important genetic risk factor for the vast majority of late onset AD cases has been linked to subjects carrying the APOE E4 allele; however, this risk factor is only represented in 50% of

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this late onset population. Here, the authors describe a previously unknown gene, Saitohin (STH), which is located in the intron between exons 9 and 10 of the human tau gene. tau codes for a microtubule-associated protein that plays an important role in the formation of neurofibrillary tangles (NFTs), another hallmark of AD-related neuropathology. A polymorphism in the STH gene appears to be overexpressed in the homozygous state in late onset AD patients, as well as in other clinical entities, such as frontotemporal dementia, Pick’s disease, and progressive supranuclear palsy, characterised by the presence NFTs. • Systemic and neurologic abnormalities distinguish the lysosomal disorders sialidosis and galactosialidosis in mice. De Geest N, Bonten E, Mann L, de Sousa-Hitzler J, Hahn C, d’Azzo A: Hum Mol Genet 2002, 11:1455-64. Significance: Development of distinct transgenic mice strains mimicking two different lysosomal neurodegenerative disorders. Findings: Deficiency of lysosomal neuraminidase (Neu) activity is associated with neurodegenerative disorders of glycoprotein metabolism, sialidosis (mucolipidosis I) and galactosidosis (GS). In contrast to the comparable lysosomal storage in the Neu1 and GS knockout mice, this study describes a distinct and severe phenotype for mice lacking the Neu1 locus. This knockout leads to deformity of the spine, high incidence of premature death, extramedullary hematopoiesis, and lack of early degeneration of cerebellar Purkinje cells. This study thus provides a better tool for the understanding of these rare diseases and for the development of targeted therapies.