Neurobiology

Neurobiology

463 Neurobiology Paper alert Selected by Jack Price Institute of Psychiatry, London, UK e-mail: [email protected] •• Conversion of cerebral cor...

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463

Neurobiology Paper alert

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

•• Conversion of cerebral cortex into basal ganglia in Emx2–/– Pax6sey/sey double-mutant mice. Muzio L, Di Benedetto B, Stoykova A, Boncinelli E, Gruss P, Mallamaci A: Nat Neurosci 2002, 5:737-745 Significance: A preliminary answer to the question of what drives the cerebral cortex to have properties distinct from those of neighbouring forebrain regions. Findings: The mammalian telencephalon is made up of a number of distinct regions: the cerebrum and basal ganglia among them. They develop from neighbouring regions of neuroepithelium. So, what are the genes that direct the two embryonic tissues to become such different structures? A number of candidates have emerged over recent years, and the authors of this study take a close look at two of them: Pax6 and Emx2. Their expression patterns plus extensive studies of their knockout phenotypes have led experimenters to suggest that these two genes play fundamental roles in specifying cortical fate. In this study, the authors look at the phenotypes of doublemutants in which both genes are knocked out. They use a series of marker genes to show that in these double-knockout mice, the cortex takes on a striatum-like structure and the cortical neurons become respecified as subpallial neurons. The conclusion they draw is that these two genes, acting along parallel pathways, promote corticogenesis. They leave open the possibility that other genes, such as Lhx2, might also be significant. Nonetheless, the broad conclusion is that fundamentally Pax6 and Emx2 make cortex different from striatum.

•• LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein–protein interactions. Thaler JP, Lee S-K, Jurata LW, Gill GN, Pfaff SL: Cell 2002, 110:237-249 Significance: An insight into the mechanism by which LIM factors determine neuronal fate in the spinal cord. Findings: Previous work has indicated that the fate of ventral spinal cord neurons is linked primarily to dorsoventral pattering. This results in adjacent groups of precursor cells acquiring distinct specifications and thereby giving rise to different populations of spinal neurons. But how are the different identities of the precursor populations translated into the different neuronal fates of their progeny? We have known for a while that members of the LIM class of homeodomain factors are involved in this specification, but their role is not simple, as each neuronal type expresses not a single specifying factor, but a number of factors. It seemed, therefore, that a combinatorial code was in operation whereby the expression of a specific combination of factors constituted a particular fate. In this study, Thaler et al. clarify the mechanism whereby a particular combination specifies one such fate choice. V2 interneurons and motor neurons are two populations of ventral cord cells that arise from neighbouring precursor populations. Both populations express the LIM factor, Lhx3 (and a related factor Lhx4), whereas only motor neurons express another LIM factor, Isl1. Both populations also express NLI, a LIM domain interacting protein. This study shows that V2 fate is driven by a tetrameric complex of proteins composed of two Lhx3 and two NLI subunits, whereas motor neuron fate is driven by a hexameric complex composed of two Lhx3, two Isl1, and two NLI subunits.

• Distinct actions of Emx1, Emx2, and Pax6 in regulating the specification of areas in the developing neocortex. Bishop KM, Rubenstein JLR, O’Leary DDM: J Neurosci 2002, 22:7627-7638. Significance: A different perspective on the actions of Emx genes and Pax6, attributing their influence on cortical development to their role in area specification. Findings: A fundamental property of mammalian cerebral cortex is that it is organised into functional areas — somatosensory, motor, visual, etc. — and the issue of what drives the process of area specification (or arealisation as it is sometimes called) has a long and chequered history in neuroscience research. Much of the discussion over many years centred on whether area specification was the result of the interaction between cortex and incoming thalamic afferents. Although there is considerable evidence for some role for thalamic axons, most recent research suggests that area specification emerges from the interaction of an intrinsic cortical program with influences from neighbouring signalling centres such as the cortical hem. This conclusion has led to a search for the intrinsic genetic factors that drive cortical area specification. Both Emx2 and Pax6 are implicated in this process for no better reason than they are expressed in a gradient across the cortical field, although for Emx2 in particular, there is already experimental data that cortical areas shift if levels of its expression are manipulated. In this study, a series of marker genes are employed that are differentially expressed across the rostrocaudal dimension of the cortical plate. Although not markers of cortical areas per se, their expression is likely to reflect the specification process. Using mouse knockouts, the authors find that in Emx2 mutants,

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 2002, 12:463–470 Contents (chosen by) 463 Development (Price) 464 Cognitive neuroscience (Silva, Kushner and Reber) 465 Signalling mechanisms (Häusser and Bezzi) 466 Sensory systems (Wood) 467 Neuronal and glial cell biology (Bredt) 467 Motor systems (Chafee and Merchant) 468 Neurobiology of behaviour (Goodwin and Kyriacou) 469 Neurobiology of disease (Kempermann and Winkler)

Development

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marker expression boundaries shift caudally, whereas in Pax6 mutants the boundaries shift rostrally. Emx1, a gene closely related to Emx2 and also expressed in the developing cortex, gives no such shifts, and serves as a useful control. The implication of this study is that Emx2 and Pax6 are part of the area specification process, acting to give cortex a more rostral or caudal identity respectively. Presumably they act antagonistically during the specification process. Considered in conjunction with the work of Muzio et al. (see above), a picture emerges of these two genes acting in concert to specify cortex and to give it its area specification. • Lobe mediates Notch signaling to control domain-specific growth in the Drosophila eye disc. Chern JJ, Choi K-W: Development 2002, 129:4005-4013. Significance: The discovery of a novel modulator of Notch signalling in insect eye development. Findings: The insect eye is composed of multiple clusters of cells called ommatidia, which are organised in mirror symmetry about a dorsoventral boundary. The boundary arises as a consequence of the expression of the morphogens wingless and decapentaplegic, which are expressed in the dorsal and ventral domains respectively. As a consequence, expression of the fringe gene becomes restricted to the ventral domain, leading to an asymmetry to the Notch signalling cascade in the dorsal and ventral domains. Notch function is required for appropriate eye growth, but how these are linked is unclear. This study presents evidence that the Lobe gene plays a role in this coupling. The authors clone and sequence Lobe and show that it mediates the proliferative effect of Notch in the ventral domain only, because loss of Lobe function specifically abolishes ventral eye growth. The function of Lobe appears to be to regulate serate, the Notch ligand already implicated in Notch signalling at the dorsoventral boundary. Lobe is a novel gene, and its sequence gives away little about its possible molecular interactions. Nonetheless, the authors present evidence for homologues in both mouse and human. Thus, we seem to have yet another new player in the ever-expanding Notch signalling cascade.

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

•• Immunization reverses memory deficits without β burden in Alzheimer’s disease model. reducing brain Aβ Dodart J-C, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM: Nat Neurosci 2002, 5:452-457. Significance: Memory deficits associated with an Alzheimer’s disease mouse model can be rapidly reversed with an anti-Aβ antibody without reducing brain Aβ deposits. Findings: Brain Aβ deposits are thought to be a critical component of the cognitive impairments associated with AD. Transgenic mice (PDAPP) overexpressing a mutant β-amyloid precursor protein show age-dependent memory deficits that are thought to model the cognitive deficits associated with Alzheimer’s disease (AD). In this study, the authors reversed these memory deficits with a monoclonal antibody (m266) directed against the Aβ peptide. Although wild-type littermates performed significantly above chance in an object recognition

task, neither 8 nor 24 month-old transgenic animals discriminated between novel and familiar objects during testing. Treatment of the 24 month-old transgenic mice with intraperitoneal injections of m266 once a week for six weeks rescued performance on the object recognition task to wild-type levels. Despite the significant behavioral improvement, this dose had no detectable effect on the percentage area occupied by Aβ deposits in the brain (Aβ burden). Additional analysis revealed no significant correlation between amyloid deposits and behavioral performance. Remarkably, a single treatment with m266, 24 hours prior to testing in the object recognition task, also rescued the cognitive deficit. A dose-response curve with m266 revealed that plasma Aβ levels were correlated with behavioral performance. Acute treatment with m266 was also effective in improving performance on a holeboard learning task. The authors conclude that the cognitive deficits in PDAPP mice are caused by the presence of a soluble Aβ species, not amyloid deposits. •• Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Nakazawa K, Quirk MC, Chitwood RA, Watanabe M, Yeckel MF, Sun LD, Kato A, Carr CA, Johnston D, Wilson MA, Tonegawa S: Science 2002, 297:211-218. Significance: NMDA receptor plasticity in the CA3 region is critical for pattern completion, the retrieval of entire memory traces from partial or degraded inputs. Findings: The auto-associative network formed by recurrent collaterals within area CA3 of the hippocampus has been suggested to serve as a mechanism for pattern completion, the retrieval of entire memory traces from partial or degraded inputs. The goal of this study was to examine the necessity of synaptic plasticity at the CA3 recurrent collateral synapses in performing a task requiring pattern completion. Taking advantage of the regional specificity of the endogenous kainate receptor 1 promoter, the authors constructed a transgenic mouse line expressing Cre recombinase and capable of deleting the NMDA receptor type 1 selectively in the CA3 region. Electrophysiological analysis in three different hippocampal subregions demonstrated a nearly complete absence of NMDA currents and a NMDA receptor-dependent synaptic plasticity deficit specifically in the CA3 region. Although performance in the standard hidden platform version of the Morris water maze was normal in mutant mice when all visual cues were present, partial removal of these cues revealed a deficit in these mice. Single unit recordings showed that although representations of place information in the CA1 region (place fields) formed normally in mutant mice, partial removal of visual cues, that presumably guide the mice to the escape platform, destabilized these representations. Thus, with their unique set of genetic tools, the authors conclude that plasticity at excitatory recurrent commissural/associational synapses, specifically within region CA3 of the hippocampus, is necessary for intact retrieval of spatial memories under conditions where only a partial subset of the original cues are available to the animal. •• The endogenous cannabinoid system controls extinction of aversive memories. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zeiglgansberger W, DiMarzo V, Lutz B: Nature 2002, 418:530-534. Significance: A novel mechanism controlling the extinction of associative fear memories through endogenous cannabinoids.

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Findings: The authors use both genetics and pharmacology to examine the role of endogenous cannabinoids (CBs) in auditory fear conditioning where animals learn to fear a neutral stimulus (a tone; conditioned stimulus [CS]) by its association with a footshock. In the first set of experiments, the authors showed that deletion of the CB1 receptor does not affect acquisition of auditory fear conditioning but substantially impairs its extinction. The impairment of extinction was significant both short-term (within daily three minute extinction sessions) and long-term (across days). Similarly, a CB1 antagonist (SR141716A) was shown to impair both short-term and long-term extinction without impairing acquisition. The authors also examined the increase in endogenous cannabinoid levels following re-exposure to the tone 24 hours after associative training. Samples from the basolateral amygdala, but not from the medial prefrontal cortex, demonstrated a specific increase in endogenous cannabinoids following re-exposure to the CS. This effect was limited to animals receiving paired tone/shock presentations on training and was not mediated by the presentation of a CS not paired with a footshock. In vitro electrophysiological analyses in amygdala slices from CB1 knockout mice demonstrated increased long-term potentiation, which appeared to be mediated by a decrease in GABAA inhibitory currents. The authors propose that the endogenous cannabinoid system facilitates extinction of aversive memories by affecting inhibitory networks in the amygdala. (See also Kempermann and Winkler pp 469.) Selected by Paul J Reber Northwestern University, Evanston, Illinois, USA e-mail: [email protected]

Requirement for hippocampal CA3 NMDA Receptors in associative memory recall. Nakazawa K, Quirk MC, Chitwood RA, Watanabe M, Yeckel MF, Sun LD, Kato A, Carr CA, Johnston D, Wilson MA, Tonegawa S: Science 2002, 297:211-218. Significance: CA3 pyramidal cells play a critical role in pattern completion in support of associative memory. Findings: Genetically engineered mice with a selective ablation of the NMDA receptor gene in pyramidal CA3 hippocampal neurons were tested for learning ability using the Morris water maze. The knockout mice acquired and retained memory of the escape route at a normal rate when a set of four spatial cues was available for orientation within the maze. However, when only a single cue was available, the knockout mice were impaired in escape performance relative to wild-type mice and also exhibited a reduction in place-related activity in CA1 pyramidal cells. This result provides strong evidence for the hypothesized role of CA3 pyramidal cells in pattern completion to support associative memory. (See also Silva and Kushner pp 464.)

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

•• Regulation of AMPA receptor lateral movements. Borgdorff AJ, Choquet D: Nature 2002, 417:649-653. Significance: A direct demonstration that single AMPA-type glutamate receptors move rapidly on the surface membrane of neurons and that the delivery of AMPA receptors to synapses may be via lateral movement from extrasynaptic locations.

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Findings: In a brilliant technical achievement, the authors monitored the movement of single AMPA receptors by coating latex beads with GluR2 AMPA receptor antibodies and tracking movement of the beads as they bound to AMPA receptors on the surface of hippocampal neurons in culture. AMPA receptors alternated between rapid random movement and stationary periods when the receptors reached a synapse. Importantly, local elevations of calcium immobilised the receptors, suggesting that a similar process may be activated by the calcium elevations that trigger synaptic plasticity. •• Directionally selective calcium signals in dendrites of starburst amacrine cells. Euler T, Detwiler PB, Denk W: Nature 2002, 418:845-52. Significance: Direct evidence that starburst amacrine cells in the retina show directionally selective local dendritic calcium signals, demonstrating that directional selectivity occurs upstream from ganglion cells and that dendrites can act as independent computational compartments. Findings: Retinal ganglion cells show direction selectivity in their responses to moving stimuli, but the origin of this selectivity has long been controversial and remains a classic problem in computational neuroscience. Here, the authors combined whole-cell recordings from the soma of starburst amacrine cells in intact rabbit retina with two-photon imaging of dendritic calcium signals. Dendrites could generate local calcium signals in response to localised light stimuli. In response to moving stimuli, individual dendritic branches could discriminate between different directions of image motion, while the somatic voltage response was not directionally selective. •• Transmitter-evoked local calcium release stabilizes developing dendrites. Lohmann C, Myhr KL, Wong RO: Nature 2002, 418:177-181. Significance: Demonstration that local calcium release from stores triggered by synaptic input stabilises dendritic structure during the period of synapse formation. Findings: The authors filled embryonic retinal ganglion cells with calcium indicators using ballistic loading and found local and global dendritic calcium increases. Local signals were shown to be due to calcium-induced calcium release (CICR) from stores triggered by synaptic activation of nicotinic acetylcholine receptors. Blocking CICR and local calcium signals caused retraction of dendrites. In contrast, global signals were insensitive to CICR blockers, but were sensitive to tetrodotoxin, which did not affect dendritic structure. Finally, focal uncaging of calcium also triggered CICR and prevented dendritic retraction, confirming that local calcium signalling regulates dendritic structure. Selected by Paola Bezzi University of Lausanne, Lausanne, Switzerland e-mail: [email protected]

• The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Tsai H, Frost E, To V, Robinson S, Ffrench-Constant C, Geertman R, Ransohoff R, Miller R: Cell 2002, 110:373-383. Significance: A chemokine CXCL1, through its receptor CXCR2, inhibits oligodendrocyte precursor migration in the developing spinal cord, thus contributing to the temporal and spatial pattern of myelination in this region. Findings: Successful myelination of the vertebrate CNS requires long-distance migration, much of which is accomplished

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by immature cells. Platelet-derived growth factor (PDGF) is a major mitogen for oligodendrocyte precursor cells (OPCs), enhances precursor motility and provides chemotactic guidance. The proliferative response of spinal cord OPCs to PDGF seems to depend on synergistic stimulation by the chemokine CXCL1. In the CNS, CXCL1 is expressed by white matter astrocytes during the time of migration of OPCs. In this paper, the authors provide evidence that CXCL1 inhibits PDGF-stimulated migration of immature spinal cord OPCs both in vivo and in vitro. They show that immature OPCs express the chemokine receptor CXCR2 and that signaling through this receptor mediates a reversible CXCL1 inhibition of migration. Moreover, in slice cultures of embryonic spinal cord, CXCL1 reduces the number of cells that migrate to dorsal regions, and, in the spinal cord white matter of mice lacking CXCR2, the number of differentiated oligodendrocytes is diminished and their distribution altered. Thus, the CXCL1/CXCR2 signal system contributes to the temporal and spatial pattern of myelination in the developing spinal cord. The authors further suggest that during migration through the white matter, OPCs encounter an environment in which astrocytes transiently express locally high levels of CXCL1, which, via the CXCR2 receptor, inhibit further migration and stimulate proliferation in concert with PDGF. •• Intracellular calcium stores regulate activity-dependent neuropeptide release form dendrites. Ludwig M, Sabatier N, Bull PM, Landgraf R, Dayanithi G, Leng G: Nature 2002, 418:85-89. Significance: The first direct evidence that local intracellular Ca2+ increase induces oxytocin release from hypothalamic dendrites without increasing electrical activity of the cell body or inducing secretion from the nerve terminals. Findings: Neurons in the supraoptic nucleus (SON) of the hypothalamus project axons to the posterior pituitary, where oxytocin and vasopressin are secreted from axonal nerve terminals into the systemic circulation. These peptides are also released in large amounts from dendrites in the SON but secretion at these two sites is not consistently correlated. Oxytocin mobilizes intracellular Ca2+ from thapsigarginsensitive stores. In this paper, the authors tested whether increasing intracellular Ca2+ is a critical step for dendritic oxytocin release. They show that direct application of thapsigargin into the rat SON causes a significant and reversible increase in local oxytocin release; subsequent systemic osmotic stimulation causes a much larger release of oxytocin in thapsigargin-pretreated animals than in controls. The potentiating effect of thapsigargin is also present in the activitydependent oxytocin release from dendrites and in the depolarization-dependent secretion of oxytocin from isolated neural lobes. Thus, mobilization of intracellular Ca2+ is followed by a long-lasting potentiation (priming) of activity- or depolarization-dependent dendritic release. To investigate the physiological significance of priming of activity-dependent dendritic release, the authors recorded from a single oxytocin neuron, while dialyzing the SON with thapsigargin. Thapsigargin had no effect on the mean electrical discharge rate of cells but statistical analyses revealed an important effect on discharge patterning. Ludwig et al. suggest that under normal conditions activity-dependent dendritic release of oxytocin may have a positive feedback effect on electrical activity. To test this hypothesis, they showed that constant collision stimulation (CCS) applied after thapsigargin treatment caused no increase in the firing rate of oxytocin cells, but did reorganize

spike activity. Finally, the effect of oxytocin on spike patterning during CCS was similar to that observed with thapsigargin.

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

•• Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord. Bao L, Wang HF, Cai HJ, Tong YG, Jin SX, Lu YJ, Grant G, Hokfelt T, Zhang X: Eur J Neurosci 2002, 16:175-185. Significance: How important is rewiring in the dorsal horn for chronic pain? Findings: Axotomy-induced sprouting of myelinated afferents (A-fibres) from laminae III–IV into laminae I–II of the spinal has been considered to be important for the structural basis of neuropathic pain. However, the cholera toxin B subunit (CTB), a neuronal tracer previously used to demonstrate the sprouting of A-fibres, also labels unmyelinated afferents (C-fibres) in lamina II and thin myelinated afferents in lamina I, when applied after peripheral nerve transection. In this paper, CTB was applied four days before axotomy (pre-injury-labelling), and sprouting was monitored after axotomy. Only a small number of A-fibres sprouted into inner lamina II making synaptic contact with dendrites. Neuropeptide Y (NPY) was found in these sprouts in inner lamina II, an area very rich in Y1 receptor-positive processes. These results suggest that axotomy-induced sprouting from deeper to superficial layers is only marginal in neuropathic preparations. The limited reorganisation involves predominantly large NPY immunoreactive dorsal root ganglion neurons sprouting into the Y1 receptor-rich inner lamina II. • Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Xiao HS, Huang QH, Zhang FX, Bao L, Lu YJ, Guo C, Yang L, Huang WJ, Fu G, Xu SH, Cheng XP, Yan Q et al.: Proc Natl Acad Sci USA 2002, 99:8360-8365. • Dorsal horn-enriched genes identified by DNA microarray, in situ hybridization and immunohistochemistry. Sun H, Xu J, Della Penna KB, Benz RJ, Kinose F, Holder DJ, Koblan KS, Gerhold DL, Wang H: BMC Neurosci 2002, 3:11. Published online at: http://www.biomedcentral.com/content/pdf/14712202-3-11.pdf. Significance: A catalogue of genes that are misregulated in peripheral neurons after axotomy, and genes that are present in second order sensory neurons of the dorsal horn. Findings: Xiao et al. examined 7523 genes and expressed sequence tags (ESTs) using 33P-labeled probes. Of these, the expression of 122 genes and 51 ESTs was strongly changed two weeks after axotomy in the rat. These genes include neuropeptides, receptors, ion channels, signal transduction molecules, synaptic vesicle proteins, and others. The upregulation of the GABAA receptor α5 subunit, the peripheral benzodiazepine receptor, the nicotinic acetylcholine receptor α7 subunit, the P2Y1 purinoceptor, the Na+ channel β2 subunit, and the Ca2+ channel α2δ1 subunit all represent interesting observations. Sun et al. conducted a large-scale screening for genes with enriched expression in the dorsal spinal cord, using DNA microarray and quantitative real-time PCR. In addition to genes known to be specifically expressed

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in the dorsal spinal cord, other neuropeptides, receptors, ion channels, and signaling molecules were also found enriched in the dorsal spinal cord. In situ hybridization and immuno histochemistry revealed the cellular expression of a subset of these genes. The regulation of a subset of the genes was also studied in the spinal nerve ligation neuropathic pain model. In general, the genes enriched in the dorsal spinal cord were not among those found to be upregulated in the spinal nerve ligation model of neuropathic pain. •• Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Shin J, Cho H, Hwang SW, Jung J, Shin CY, Lee SY, Kim SH, Lee MG, Choi YH, Kim J et al.: Proc Natl Acad Sci USA 2002, 99:10150-10155. Significance: Gating of the capsaicin receptor TRPV1 by bradykinin via lipid second messengers provides yet another mechanism for sensory neuron activation via this channel. Findings: The capsaicin-sensitive vanilloid receptor TRPV1 plays an important role in inflammatory pain (hyperalgesia), but the underlying mechanism is unknown. This study demonstrates that bradykinin, acting at B2 bradykinin receptors, excites sensory nerve endings by activating capsaicin receptors via production of 12-lipoxygenase metabolites of arachidonic acid. This finding identifies a mechanism that might be targeted in the development of new therapeutic strategies for the treatment of inflammatory pain. •• Annexin II light chain regulates sensory neuron-specific sodium channel expression. Okuse K, Malik-Hall M, Baker MD, Poon WY, Kong H, Chao MV, Wood JN: Nature 2002, 417:653-656. •• p11, an annexin II subunit, an auxiliary protein associated with the background K(+) channel, TASK-1. Girard C, Tinel N, Terrenoire C, Romey G, Lazdunski M, Borsotto M: EMBO J 2002, 21:4439-4448. Significance: Demonstration that the annexin light chain p11 plays a crucial role in the regulation of receptor trafficking for the voltage-gated sodium channel Nav1.8 and the two-pass potassium channel TASK1. Findings: Annexin II light chain p11 is a regulatory factor that facilitates the expression of Nav1.8. p11 binds directly to the amino terminus of Nav1.8 and promotes the translocation of Nav1.8 to the plasma membrane, producing functional channels. The endogenous Nav1.8 current in sensory neurons is inhibited by antisense downregulation of p11 expression. p11 also interacts specifically with the TASK1 K+ channel. This association with p11 requires the integrity of the last three carboxy-terminal amino acids, Ser–Ser–Val, in TASK1. Association with p11 is essential for trafficking of TASK1 to the plasma membrane. p11 association with the TASK1 channel masks an endoplasmic reticulum retention signal identified as Lys–Arg–Arg that precedes the Ser–Ser–Val sequence. This novel role of p11 adds another unsuspected function to the many roles of annexin subunits.

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

•• Regulation of AChR clustering by dishevelled interacting with MuSK and PAK1. Luo Z, Wang Q, Zhou J, Wang J, Luo Z,

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Liu M, He X, Wynshaw-Boris A, Xiong W, Lu B, Mei L: Neuron 2002, 35:489. Significance: Description of the cellular signaling cascade that mediates acetylcholine receptor clustering in response to agrin. Findings: Previous studies have shown that agrin binding to a muscle specific kinase (MuSK) induces clustering of acetylcholine receptors (AChRs) at neuromuscular junctions; however, the cellular mechanism for this has been uncertain. This study shows that MuSK binds to dishevelled, which in turn interacts with a downstream kinase PAK1. Disrupting these interactions or inhibiting PAK1 activity attenuates AChR clustering in Xenopus myocytes or cultured mammalian myotubes. These results identify important roles for dishevelled and PAK1 in agrin-induced AChR clustering. •• Subunit-specific NMDA receptor trafficking to synapses. Barria A, Malinow R: Neuron 2002, 35:345. Significance: Definition of the subunit-specific rules governing NMDA insertion into hippocampal neurons. Findings: Using optically and electrophysiologically tagged NMDA receptor subunits infected into hippocampal slice neuronal cultures, the authors determine the rules that control synaptic incorporation of these receptors. NR1 subunits do not go to synapses alone, they are driven to synapses by coexpression with either NR2A or NR2B subunits. During normal development, NR2A receptors replace NR2B receptors and this requires synaptic activity. Interestingly, glutamate binding to NR2B rather than calcium influx through the receptor is essential for replacement. Thus, as with AMPA receptors, subunit-specific trafficking determines the synaptic expression of NMDA receptors. • Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal sites. Ostroff L, Fiala J, Allwardt B, Harris K: Neuron 2002, 35:535. Significance: Demonstration that the protein synthesis machinery redistributes to synaptic spines during long-term potentiation. Findings: To assess the presence of polyribosomes in dendritic spines as a potential indicator of increased local protein synthesis in synaptic plasticity, the authors assessed the ultrastructure of synapses in hippocampus before and after long-term potentiation (LTP). The authors found a dramatic increase in the percentage of spines containing polyribosomes following LTP and a commensurate loss of polyribosomes from dendritic shafts. Furthermore, the spines containing polyribosomes showed enlarged postsynaptic densities. These studies suggest that increased protein synthesis during LTP may modulate synaptic morphology and contribute to changes in synaptic strength.

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

• Training and synchrony in the motor system. Schieber MH: J Neurosci 2002, 22:5277-5281. Significance: Synchronization among cells with connections to spinal motoneuron pools is larger in monkeys trained to perform finger and wrist movements for long periods of time than in a monkey trained for less than a year.

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Findings: The activity of neurons in the motor cortex and the electromyogram (EMG) of forearm and hand muscles were recorded in two sets of monkeys. One set was trained for more than five years to perform 12 finger and wrist movements, the other was trained for less than a year to perform six finger movements. The results show; first, that the spike-triggered averages (STAs) of the EMG were more prevalent in monkeys with longer training; second, in the monkey with shorter training, most of the STAs had onset latencies and peak widths corresponding to relatively pure postspike effects; and third, the majority of the STAs of monkeys with longer training had an onset latency that was too early and a peak width that was too wide to represent a pure postspike effect from the trigger neuron. This last result indicates that other neurons, also connected to the motoneuronal pool, discharge in synchrony with the recorded motor cortical cell. • A real-time state predictor in motor control: study of saccadic eye movements during reaching movements. Ariff G, Donchin O, Nanayakkara T, Shadmehr R: J Neurosci 2002, 22:7721-7729. Significance: Immediately after a brief perturbation of the hand, the brain is able to predict where the limb will be in the near future. Saccades are an unbiased, real-time estimator of this prediction. Findings: Human subjects performed unseen reaching movements while tracking with the eyes the hand trajectory without visual feedback. In unperturbed reaching movements, the saccade at time t provided an unbiased estimate of the hand position at t + 196 ms. When a 50 ms random force perturbation to the moving hand was applied, the saccades showed the following: a sharp inhibition at 100 ms after perturbation, and a large increase of occurrence at 170 ms after perturbation. These saccades were an unbiased estimator of the hand position at saccade time t + 150ms. These results suggest that the eye behavior during reaching is an indicator that the brain computes an estimate of the future limb position, based on an internal model that depends on real-time proprioceptive feedback. • Adaptation to a visuomotor shift depends on the starting posture. Baradac P, Wolpert DM: J Neurophysiol 2002, 88:973-981. Significance: Evidence that motor adaptation corrects movement in a manner that is dependent upon the joint angles that specify the posture of the entire limb, and not just the limb endpoint. Findings: In learning to compensate for an artificial change in visual feedback, the motor system might adapt to this change by recalibrating movement trajectories with respect to hand position, or with respect to the joint angles that specify the trajectory. In this study, subjects produced pointing movements to a target in a virtual three-dimensional display. Visual feedback of finger position was provided (on some trials). Subjects learned to hit the target after an offset was introduced between actual and displayed finger position. They were unaware of this adaptation. After adapting to the change in visual feedback while making the reach from one starting arm posture, the subjects were tested with different initial arm postures. The start and end points of the movements, and thus the path of the hand through space, were constant in all cases. The interesting result was that the adaptation of the subjects was specific for the starting arm posture. The degree of adaptation that was seen was a function of the difference between a given starting arm posture, and the starting posture adopted while adaptation was initially acquired. This indicates that motor adaptation modified the

visuomotor transformation in a circumscribed region of joint space, and that when the subject was forced to produce the same hand movement through different arm postures, adaptation broke down.

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]

•• Identification of genes involved in Drosophila melanogaster geotaxis, a complex behavioral trait. Toma DP, White KP, Hirsch J, Greenspan RJ: Nat Genet 2002, 31:349-353. Significance: Identification of the single genes that contribute to a complex phenotypic behavioural character, using microarray analysis of bidirectionally selected lines. Findings: At the dawn of experimental behaviour genetics in the 1950s, Jerry Hirsch and his collaborators, using specially designed mazes, selected for lines of Drosophila melanogaster that were either positively (moving towards gravity) or negatively geotactic. The selection was slow, evidently because variation at many loci was reshuffled and selected at each generation, and chromosome substitution analyses revealed that genes spread over the entire genome were contributing to differences in this behaviour. Forty years later, Greenspan and his colleagues obtained Jerry Hirsch’s lines, that had been reselected, and applied cDNA microarrays to two lines showing opposite geotactic behaviour. About 250 genes showing consistent differential expression in the two lines were identified, and a small number were validated with qPCR. Studying the behaviour of existing mutants in four genes that gave differences between the lines, confirmed the array results at a functional level in three genes, cryptochrome, pigment-dispersing factor, and pendulin, which encodes a nuclear importin. Interestingly, the first two genes are implicated as input and output factors respectively in the circadian mechanism. These results are interesting in themselves, but as a concept, the use of microarrays to dissect polygenic traits that have been initially revealed by selection experiments, marries the classic quantitative approach to behavioural genetics, with the modern pragmatic single gene approach to dissecting the nervous system. •• The orphan nuclear receptor REV-ERB alpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Preitner N, Damiola F, Molina LL, Zakany J, Duboule D, Albrecht U, Schibler U: Cell 2002, 110:251-260. Significance: Rev-erbα is the molecule that connects the two regulatory pathways, composed of at least one negative feedback loop coupled to a feedforward pathway, in the mammalian circadian clock. Findings: Circadian rhythms in mammals are driven by a molecular oscillator located in the suprachiasmatic nuclei (SCN). Major components of the oscillator include the mPer and mCry genes, whose transcripts cycle in abundance with a 24 h period, and mClock and Bmal1, whose transcripts also cycle. mCRY acts as a negative autoregulator and represses both mPer and mCry transcription, whereas mPER and perhaps mCRY may act as positive regulators for Bmal1 gene expression.

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This interlocking of positive and negative loops stabilises the clockworks, and generates cycles for the mPer/mCry and Bmal1 transcripts that are in antiphase. Very little is known about how the Bmal1 cycle is generated, but its promoter contains putative binding sites for ROR and REV-ERB orphan nuclear receptors, and mobility shift assays using these sequences reveal cycling protein–DNA complexes from mouse liver extracts. Levels of Rev-erbα mRNA showed diurnal cycling in the SCN, and protein cycling in the liver, but in antiphase to Bmal1 cycling, suggesting that REV-ERB is the negative regulator of Bmal1. In transgenic Rev-erbα knockout mice, Bmal1 transcript cycling was dramatically reduced in both liver and SCN, and some disruption was seen in both the mClock and mCry1 cycles, but protein cycles in the latter two molecules were hardly affected. The mutant mice showed slightly longer free-running periods, but no major defects in their wheel-running activity, suggesting that transcript cycles of Bmal1 are not critical for rhythmic behaviour per se, although more dramatic effects were seen in the mutant circadian phase-shifting by light pulses. Further genetic analysis revealed that Rev-erbα is repressed by mPER protein, thereby activating Bmal1 transcription. As the Rev-erbα promoter contains three E-boxes (targets for the BMAL1mCLOCK bHLH regions), then mCLOCK-BMAL1 would also be the activators of Rev-erbα, a suggestion that is supported by several other lines of circumstantial evidence. Thus, REV-ERBα couples the negative to the positive limb of the molecular oscillator in the mammal.

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]

• Mice with truncated MECP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Shahbazian MD, Young JI, Yuva-Paylor LA, Spencer CM, Antalffy BA, Noebels JL, Armstrong DL, Paylor R, Zoghbi HY: Neuron 2002, 18:243-254. Significance: The unusual case of a murine model for an extremely complex human disorder that even mimics surprising details. Findings: Rett syndrome (RTT) is a complex pediatric syndrome, caused by mutations in the methyl–CpG binding protein 2 (MECP2). Surprisingly, dysfunction of MECP2 protein, which interacts with the histone deacetylase repressing gene transcription, leads to a primarily neurological phenotype. To retain partial MECP2 function, the authors generated a mouse with a truncated MECP2 gene. These mice showed numerous symptoms found in RTT, from myoclonic seizures, tremor, hypoactivity, and kyphosis to stereotyped forelimb movements as the murine equivalent to the characteristic handwringing movements seen in humans with RTT. Cognitive parameters, such as watermaze learning and fear conditioning were normal. Mutant mice had elevated tissue-specific acetylation of histone H3, suggesting that the mutants have an impaired chromatin structure. Importantly, the mouse model was generated in males, where it would not be confounded by X-chromosome inactivation. •• The endogenous cannabinoid system controls extinction of aversive memories. Marsicano G, Wotjak CT, Azad SC,

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Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W et al.: Nature 2002, 418:530-534. Significance: An exploration of how we can forget unwanted memories. Findings: The molecular mechanisms underlying the extinction of (aversive) memories are largely known. Mice deficient of the (endo-) cannabinoid receptor 1 (CB1) showed severe impairments in memory extinction in auditory fear-conditioning tasks, whereas memory acquisition was normal. Treating wild-type mice with a CB1 antagonist mimicked the mutant phenotype. A side experiment showed that indeed during the extinction trial of the test, endocannabinoid levels were elevated in brain tissue. In the amygdala of CB1–/– mice, electrophysiological correlates of learning (long-term potentiation) were more pronounced, whereas correlates of inhibitory function (long-term depression of inhibitory postsynaptic currents) were abolished. The authors conclude that endocannabinoids selectively inhibit inhibitory connections in the amygdala. This is an important paper with many implications for psychiatry and with a great general appeal due to its exploration of how to forget unwanted memories. (See also Silva and Kushner pp 464.) • 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 2002,22:5198-203. Significance: A clever experimental design allowing assessment of cognitive slowing in Parkinson’s disease without confounding the test with the dominating motor impairment. Findings: In this study, Parkinson’s disease (PD) patients without bradykinesia (slowness of movements, one of the possible motor symptoms of PD) were examined and were presented with a series of visual stimuli, on which they had to react by performing a mental operation. Both patients and control subjects became worse with increasing speed of the test, but PD patients performed with significantly lower accuracy than controls. The study indicates that the decrease in the speed of performing a given task, as seen in PD patients, is not restricted to motor function, but also affects cognitive systems. This finding is important, because the issue of whether PD patients are genuinely slower in cognitive processing and thus whether or not such symptoms would potentially benefit from particular therapeutic attention has been a subject of long debate. • Evidence for a genetic association between monoamine oxidase A and restless legs syndrome. Desautels A, Turecki G, Montplaisir J, Brisebois K, Sequeira A, Adam B, Rouleau GA: Neurology 2002, 59:215-219. Significance: Another step towards a better understanding of the involvement of the dopamine system in restless legs syndrome. Findings: Restless legs syndrome (RLS) is associated with a predominant nocturnal, unpleasant aching and drawing sensation of the calves and thighs that is shortly suppressed by moving the legs. This compulsion periodically interrupts sleep and is ultimately irresistible. In particular, the therapeutic efficacy of dopaminergic-mimetic drugs suggests the involvement of the dopaminergic system in this syndrome. This population-based study links genetic variations of the monoamine oxidase A (MAOA) gene to RLS. In particular, the functional variable tandem repeat polymorphism that was recently identified in the MAOA gene promoter region

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resulting in an elevated MAOA activity was correlated with the severity of RLS symptoms. No association of RLS with the MOAB gene was detected. • An in vitro model of Parkinson’s disease: linking mitochondrial impairment to altered α-synuclein metabolism and oxidative damage. Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M, Panov AV, Cookson MR, Greenamyre JT: J Neurosci 2002, 22:7006-7015. Significance: An in vitro model links several etiologic factors implicated in PD pathogenesis and may provide a good tool to test future therapeutic agents for the treatment of PD. Findings: Sherer et al. developed a chronic in vitro PD model based on exposing human neuroblastoma cells to a low concentration of rotenone, a naturally occurring compound that is used as an insecticide and specifically inhibits the activity of complex I of the mitochondrial electron transfer chain. Treatment with rotenone lasting four weeks increased levels of insoluble α-synuclein and ubiquitin and was paralleled by an increased occurrence of apoptosis and higher vulnerability to further oxidative challenge. These results provide evidence that chronic low-grade complex I inhibition may be sufficient to mimic several important mechanisms leading to PD.

• Neuroprotective effects of glial cell line-derived neurotrophic factor mediated by an adeno-associated virus vector in a transgenic animal model of amyotrophic lateral sclerosis. Wang LJ, Lu YY, Muramatsu S, Ikeguchi K, Fujimoto K, Okada T, Mizukami H, Matsushita T, Hanazono Y, Kume A et al.: J Neurosci 2002, 22:6920-6928. Significance: Another promising attempt to deliver the most potent trophic factor for motoneurons, glial cell line-derived neurotrophic factor, to an in vivo model of amyotrophic lateral sclerosis-related awaiting to be confirmed in the clinic. Findings: At present, there is no effective therapy available to cure amyotrophic lateral sclerosis (ALS), a fatal neurological disorder caused by progressive spinal motoneuron degeneration. To test the efficacy of the adeno-associated virus (AAV) gene delivery approach for glial cell line-derived neurotrophic factor (GDNF), the authors used transgenic mice overexpressing the mutant Cu/Zn superoxide dismutase gene that is linked to a subtype of familial ALS. Intramuscular AAV–GDNF injections resulted in an increased synthesis of GDNF in the muscles associated with retrograde transport to the corresponding spinal motoneurons. More importantly, transgene expression prevented the loss of motoneurons leading to a delayed onset and attenuated manifestation of motor symptoms.