Neurobiology

Neurobiology

619 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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619

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 2002, 12:619–625 Contents (chosen by) 619 Development (Price) 620 Cognitive neuroscience (Reber) 620 Signalling mechanisms (Häusser and Bezzi) 621 622 622 623 624

Sensory systems (Wood) Neuronal and glial cell biology (Bredt) Motor systems (Chafee and Merchant) Neurobiology of behaviour (Goodwin and Kyriacou) Neurobiology of disease (Kempermann and Winkler)

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

• Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Shen Q, Zhong W, Jan YN, Temple S: Development 2002, 129:4843-4853. Significance: An important clarification of the role of Numb in neurogenesis. Findings: There is considerable evidence that in mammals, just as in invertebrates, neurogenesis is linked to the symmetry or asymmetry of neuroblast divisions. Similarly, it seems likely that Notch signaling is involved, with the modulation of Notch by Numb being a part of the regulatory mechanism. Nonetheless, the data on how these elements fit together has been confusing. Reports on the distribution of Notch at mitosis in the ventricular zone (VZ) have been contradictory. One report suggested that Numb was localized to the apical pole of the dividing VZ cells and was preferentially inherited by the daughter cell destined to remain a precursor. This was confusing as models of lateral inhibition would tend to suggest that Notch activity should remain active in precursor cells but be downregulated in differentiating cells. So Numb, which has been reported to attenuate Notch activity, should end up in the differentiating cell rather than in the dividing precursor cell where it was found. This new study is an important step in clarifying this position. It takes a single-cell culture approach to look at the expression of Numb, how it localizes following division, and the fate of cells. The authors report three important associations. First, asymmetry of Numb distribution is associated with asymmetry of division. Second, where Numb is differentially distributed between daughters, then the Numb+ cell is preferentially fated to differentiate whereas the Numb–

cell tends to be a precursor. Third, sister cells with asymmetrically distributed Numb tend to be less alike morphologically than sisters that share Numb. These observations suggest that when a cell inherits Numb it is indeed more likely to differentiate, in line with what we have learnt from other systems. The question that remains is how does this work in vivo if Numb is truly localized to the apical pole of the dividing cell, as it appears to be in the wrong place? Either that observation is misleading or VZ cells undergo some convoluted cytokinetic choreography. I think we need a clever microscopist with a time-lapse rig to tell us the answer. • BDNF release from single cells elicits local dendritic growth in the nearby neurons. Horch HW, Katz LC: Nat Neurosci 2002, 5:1177-1184. Significance: An analysis of the local dendritic effects of the neurotrophin, brain derived neurotrophic factor (BDNF). Findings: How is dentritic arborization and synapse formation regulated at a local level? Clearly, this is a profound question for both development and the ongoing regulation of synaptic number and density that underlies the dynamics of neuronal plasticity. One candidate for a role in regulating the microcircuitry is the neurotrophin, BDNF. A body of evidence suggests that this factor has morphogenic properties, and its activity-dependent release makes it a strong candidate for a ‘synaptic morphogen’. This raises the question of how the factor works at the local synaptic level. In this study, the authors used a cortical slice preparation into which they transfected genes using the gene gun. This allowed them to generate both ‘donor’ neurons, expressing red fluorescent protein (RFP) plus an epitope-tagged BDNF (or any other potential effector gene), and ‘recipient’ neurons that carried just green fluorescent protein (GFP) and were to be found at variable distances from the red donor neurons. Using two-photon confocal microscopy, the authors could then analyze variables such as dendritic length and branching in recipient neurons and relate them to their distance from donor cells. They discovered increased dendritic branching in recipient cells, but only if they were within 4.5µm of the BDNF-producing donor cells. They failed, however, to find any effect on recipient cell axons or spines. The effect was specific, in as much as tagged-NGF could not substitute for tagged-BDNF, as it could be abolished by transfecting a dominant-negative TrkB construct into the recipient cells. These data fit largely with what we thought the effects of BDNF might be at the level of the synapse, but this elegant study shows us directly what could actually be happening at that sub-cellular level. • Reelin, Disabled 1, and β1 integrins are required for the formation of the radial glial scaffold in the hippocampus. Förster E, Tielsch A, Saum B, Weiss KH, Johanssen C, Graus-Porta D, Müller U, Frotscher M: Proc Natl Acad Sci USA 2002, 99:13178-13183. Significance: An alternative role for reelin in its effect on neuronal migration. Findings: Reelin is an extra-cellular matrix molecule that is known to influence neuronal migration in the developing

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cerebrum and cerebellum. Its effect is thought to be primarily neuronal, via binding to the VLDL receptor and apolipo protein E receptor 2, and the intracellular adaptor protein to which these receptors bind, Disabled 1 (Dab 1). Reelin is also reported to bind to β1-integrins, probably on both neurons and glia. This study suggests that Reelin may not exert all of its effect on neuronal migration via its direct effect on neurons but may act by regulating the development of the radial glial scaffold, along which tangential neuronal migration is facilitated. The authors show that the normal radial glial scaffold fails to form in reeler mutants (lacking Reelin) and in scrambler mutants (lacking Dab1). They suggest that this might be attributable to a direct effect on the radial glial cells themselves.

Cognitive neuroscience Selected by Paul J Reber Northwestern University, Evanston, Illinois, USA e-mail: [email protected]

Signal-driven computations in speech processing. Pena M, Bonatti LL, Nespor M, Mehler J: Science 2002, 298:604-607. Significance: Transitional probabilities and subliminal word-boundary cues are shown to be effective speech segmentation cues for adults listening to an artificial continuous speech stream. Findings: A crucial aspect of the developmental acquisition of language is the ability to segment a continuous speech stream into constituent words. The authors demonstrate that transitional probabilities are sufficient for acquiring word boundaries in a 10-minute familiarization period when the structure of the words is highly predictable. When words have more complex structure (e.g. the first element only predicts the third element), 25 ms (subliminal) speech gaps are necessary and sufficient cues to word transitions. These results suggest a computational mechanism for speech segmentation and suggest that adults and infants acquiring language are able to perform this type of powerful statistical computation. Segmenting nonsense: an event-related potential index of perceived onsets in continuous speech. Sanders LD, Newport EL, Neville HJ: Nat Neurosci 2002, 5:700-703. Significance: Event-related potentials occurring in response to nonsense words (that have been learned) in a continuous stream are found to differ at 100ms after speech onset. Findings: Participants initially listened to a continuous stream of nonsense words with no cues provided for the word boundaries to provide a baseline of brain activity, assessed with event-related potentials (ERPs). Participants were then familiarized with six novel words through a 20 min listening period. After learning the six words, a differential response was observed in the N100 component elicited during the continuous speech, indicating a difference in processing at 100ms after speech onset. This effect was most pronounced in the best learners, and suggests that they were able to identify and attend more effectively to the first syllable of the novel words within continuous speech after the words had been learned. Coordinated reactivation of distributed memory traces in primate neocortex. Hoffman KL, McNaughton BL: Science 2002, 297:2070-2073.

Significance: Task-directed coherent neural firing was found to be reactivated during rest activity in macaques, suggesting the reactivation of a memory trace after task completion. Findings: Using four arrays of 144 microelectrodes each, network neuronal firing activity was recorded in posterior parietal cortex, motor cortex, somatosensory cortex and dorsal prefrontal cortex in macaques performing a sequential reaching task. Recordings were additionally taken during rest periods immediately preceding or following task performance. Coherent neural activity during the task was found to be recapitulated in the rest period following task performance. This result provides the first evidence for the trace reactivation hypothesis of memory consolidation in primates. Evidence for perceptual ‘trapping’ and adaptation in multistable binocular rivalry. Suzuki S, Grabowecky M: Neuron 2002, 36:143-157. Significance: Perceptual alternations in multistable binocular rivalry can show systematic patterns in the transition from one percept to another rather than being completely stochastic. Findings: Observers viewed dichoptic images that produced four distinct multistable percepts, which they reported during viewing. The results suggested that spontaneous perceptual transitions tend to get trapped between a pair of related shapes and also that during trapping, the probability of continued dominance of a trapping pair gradually decreased, indicating on-line adaptation to perceptually selected patterns. These results are the first demonstration that spontaneous alternations of visual awareness during binocular rivalry can be strongly path dependent and that the path dependence is influenced both by the coding of the perceived shapes and by adaptation.

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

•• Neurotrophin-evoked depolarization requires the sodium channel NaV1.9. Blum R, Kafitz KW, Konnerth A: Nature 2002, 419:687-693. Significance: This study demonstrates that rapid excitation evoked by neurotrophins, such as brain-derived neurotrophic factor (BDNF), depends on the activation of a unique voltage-insensitive, TTX-resistant sodium channel, NaV1.9. Findings: The authors demonstrate that the excitation of hippocampal pyramidal neurons by BDNF is sensitive to saxitoxin, implicating the involvement of a sodium channel. The response of a cell line to BDNF was abolished by applying antisense mRNA to either TrkB receptors or NaV1.9. This was confirmed by reconstitution of the BDNF-evoked current in HEK-293 cells expressing TrkB and NaV1.9, indicating that this combination is both necessary and sufficient to account for neurotrophin-evoked excitation at the molecular level. • Activity-dependent regulation of HCN pacemaker channels by cyclic-AMP: signalling through dynamic allosteric coupling. Wang J, Chen S, Nolan MF, Siegelbaum SA: Neuron 2002, 36:451-461. Significance: This study demonstrates the activity-dependent regulation of the affinity of HCN channels for cAMP, thus

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providing a novel regulatory mechanism that integrates activity over several seconds even in the absence of changes in levels of second messengers. Findings: cAMP facilitates activation of Ih — which is mediated by hyperpolarization-activated, cation-non-selective (HCN) channels — by shifting the activation curve for these channels to more depolarized levels. The authors show that Ih evoked in relatively low concentrations of cAMP reveals a time-dependent effect of this second messenger, suggesting a gating scheme in which hyperpolarization can both directly open HCN channels and increase the channels’ affinity for cAMP. The cAMP-bound open state contributes to a slowly deactivating conductance that can sum during prolonged periods of hyperpolarization. This mechanism allows for dynamic cAMP-dependent signalling although the concentration of this second messenger is static. • Kainate receptors differentially regulate release at two parallel fiber synapses. Delaney AJ, Jahr CE: Neuron 2002, 36:475-482. Significance: This study demonstrates differential, frequencydependent regulation of excitation and inhibition onto Purkinje cells (PCs) by presynaptic kainate receptors, providing a potential mechanism for a cerebellar ‘gear-shift’. Findings: The authors show that the kainate receptor (KAR) agonist domoate acts on parallel fiber synapses onto PCs and stellate cells (SCs). Dose-response relationships show that both synapses are initially facilitated and then depressed as the concentration of domoate is increased, with SC synapses depressed at 10-fold lower concentrations. Domoate does not affect responses to exogenously applied glutamate but modulates paired-pulse responses, which points towards a presynaptic site of KAR. Synaptic stimulation leads to frequencydependent facilitation/depression at PC’s and SC’s synapses, which can provide a mechanism for changing the ratio of excitation and inhibition in the behaving animal. • A photoactivatable GFP for selective photolabelling of proteins and cells. Patterson GH, Lippincott-Schwartz J: Science 2002, 297:1873-1877. Significance: This study provides a new tool for examining the distribution, targeting and dynamics of intracellular and membrane proteins, and for tagging specific neuronal subpopulations. Findings: The authors report a variant of green fluorescent protein (GFP) that shows a rapid and large (100-fold) increase in fluorescence using 488 nm excitation following intense excitation at 413 nm. The increase is stable over many days, and the function of chimeric proteins does not appear to be affected. This provides a novel means to label and track the fate of specific proteins in subcellular compartments, which is preferable to photobleaching due to the absence of signal from newly synthesized proteins. Selected by Paola Bezzi University of Lausanne, Lausanne, Switzerland e-mail: [email protected]

• ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Beattie MS, Harrington AW, Lee R, Kim JY, Boyce SL, Frank ML, Bresnahan JC, Hempstead BL, Yoon SO: Neuron 2002, 36:375-386. Significance: Neurotrophin receptor p75 is required for oligodendrocyte death following spinal cord injury and its effect is mainly mediated through Pro-NGF. These findings suggest that Pro-NGF/p75 signalling is a major pathway of oligodendrocyte apoptosis after spinal cord injury.

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Findings: Previous studies have demonstrated that the neurotrophin receptor p75 is induced by various injuries in the nervous system but its role after injury is already unclear. It is also well established that neurotrophins are induced by pathological conditions that are known to cause p75 induction. It has recently been discovered that the unprocessed NGF precursor, proNGF, binds p75 and that this selective binding leads to apoptotic death of cells that expressed this receptor. The authors investigated whether expression of p75 and proNGF was responsible for injury-mediated apoptosis of oligodendrocytes in vivo, using spinal cord injury as a model. They reported that p75 and proNGF were both induced following spinal cord injury and that p75 expression was specifically induced in oligodendrocytes. Moreover, the p75 positive cells were also positive for caspase 3, suggesting that they were undergoing apoptosis. The crucial role of p75 in oligodendrocyte apoptosis after spinal cord injury was confirmed in p75–/– mice in which apoptosis of oligodendrocytes was attenuated and their survival enhanced. Finally, they demonstrated that proNGF, which is also induced by spinal cord injury, was active in inducing apoptosis among oligodendrocytes and its action could be blocked by a specific pro-NGF antibody. • Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M: Cell 2002, 110:429-441. Significance: Activation of endogenous progenitors with EGF and FGF-2 leads to massive regeneration of hippocampal pyramidal neurons after ischemic brain injury. Findings: The discovery of neural progenitors in the adult central nervous system has raised the exciting possibility that these cells may be of therapeutic value in treating neurological diseases. However, it is not yet clear how their regenerative potential can be effectively harnessed to treat neural damage. The adult hippocampus, a vital center for learning and memory, is vulnerable to various insults such as ischemia. Although the hippocampus is known as an active neurogenic site, only one neuronal subtype — granule cells in the dentate gyrus — are continuously generated, and the production of new neurons in other hippocampal regions appears to be very limited in the adult. It is well known that transient ischemia of the forebrain in rodents causes selective degeneration of hippocampal CA1 pyramidal neurons. Using the above rat model for brain injury, the authors showed that the infusion of the growth factors EGF and FGF-2 into the lateral ventricle induced proliferation of endogenous progenitors and their differentiation into neurons after ischemia. They examined which cells were involved in the regenerative event and suggested that the progenitors present in both the periventricular region and parenchyma participated. Importantly, Nakatomi et al. also showed that the new neurons could survive for a long period of time, receive synaptic inputs and thus participate in the reconstruction of the intrahippocampal connection.

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

•• COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning,

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structure, and expression. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL: Proc Natl Acad Sci USA 2002, 99:13926-13931. Significance: The discovery of a splice variant of cyclooxygenase in the central nervous system that is blocked by compounds such as dipyrone or acetaminophen (paracetomol) finally resolves the mystery of the mechanism of action of these analgesic drugs. Findings: Cyclooxygenase enzymes COX-1 and COX-2 catalyze prostaglandin synthesis from arachidonic acid and are the targets of aspirin-like drugs. This paper describes new splice variants of COX-1, named COX3 and pCOX-1 proteins, that retain intron 1of COX-1 in their mRNAs. pCOX-1 proteins also contain an in-frame deletion of exons 5–8. COX-3 and pCOX mRNAs are expressed in cerebral cortex and in lesser amounts in other tissues. Intron 1 is conserved in mammalian COX-1 genes and inserts 30–34 amino acids into the hydrophobic signal peptide. The signal peptide is not cleaved from either protein. COX-3, but not pCOX-1a, possesses glycosylation-dependent cyclooxygenase activity. The activity of this isoform is inhibited by analgesic drugs such as acetaminophen, phenacetin, and dipyrone, as well as by conventional NSAIDs. Thus, COX-3 is likely to represent the site of action of these useful analgesic drugs, and presents an appealing new analgesic drug target to the pharmaceutical industry. •• Neurotrophin-evoked depolarization requires the sodium channel NaV1.9. Blum R, Kafitz KW, Konnerth A: Nature 2002, 419:687-693. Significance: The first demonstration of ligand-dependent activation of a voltage-gated sodium channel is provided by this study of the actions of brain derived neurotrophic factor (BDNF) on NaV1.9. Findings: BDNF and other neurotrophins have a range of actions, from trophic support to the regulation of synaptic plasticity. Activity-dependent release of BDNF occurs pre-synaptically as well as post-synaptically in CNS neurons; a role for BDNF in the establishment of long-term potentiation (LTP) and learning and memory formation has been suggested by the phenotype of BDNF-tissue-specific knock-out mice; and most recently, BDNF has been proposed to have a role as a neurotransmitter. Dendritic spines have been claimed to be sensitive sites for the BDNF-evoked excitation, and in hippocampal dentate granule cells, induction of BDNF-mediated LTP occurs post-synaptically. In this study, low nanomolar concentrations of BDNF acting through its high affinity receptor TrkB are shown to depolarize hippocampal neurons in milliseconds through activation of NaV1.9. This is an unusual tetrodotoxin-resistant sodium channel previously thought to be expressed exclusively in peripheral sensory neurons. The channel is inactive when expressed in heterologous cell lines, and is only detectable when TrkB is co-transfected with the channel transcript and BDNF is applied to the cells. This remarkable finding implies a completely new mechanism for gating NaV1.9 through ligand interactions rather than voltage activation, resulting in an activated channel with unique pharmacology (resistant to tetrodotoxin but sensitive to saxitoxin).

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

•• Treatment of ischemic brain damage by perturbing NMDA receptor interactions. Aarts M, Liu Y, Liu L, Besshoh S,

Arundine M, Gurd JW, Wang YT, Salter MW, Tymianski M: Science 2002, 298:846-850. Significance: This study demonstrates that disruption of NMDA receptor interactions with PSD-95 can prevent brain injury after stoke. Findings: The authors developed inhibitor peptides that will readily cross cell membranes and disrupt interaction of PSD-95 with the NMDA receptor. Treating cultured neurons with these peptides selectively prevents stimulation of nitric oxide synthase associated with NMDA receptor activity. Additionally, these peptides protect cultured neurons from NMDA receptor mediated cell death. Furthermore, application of these peptides before or 1 hour after an insult reduced focal ischemic brain damage in rats. •• A transmembrane motif governs the surface trafficking of nicotinic acetylcholine receptors. Wang JM, Zhang L, Yao Y, Viroonchatapan N, Rothe E, Wang ZZ: Nat Neuroscience 2002, 5:963-970. Significance: The first transmembrane domain in the α-subunit of nicotinic acetylcholine receptors ensures surface trafficking of only functional AChRs. Findings: The authors find that surface expression of nicotinic acetylcholine receptors (nAChR) is controlled by an endoplasmic reticulum retention signal in the first transmembrane domain of the α-subunit. This signal promotes degradation of unassembled receptors. Masking of this signal in mature AChR promotes surface expression of functional receptors.

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

• Coding of smooth eye movements in three-dimensional space by frontal cortex. Fukushima K, Yamanobe T, Shinmei Y, Fukushima J, Kurkin S, Peterson B: Nature 2002, 419:157-162. Significance: Whereas it is classically considered that vergence and smooth pursuit eye movements are controlled by separate brain mechanisms, this study demonstrates that the two signals are combined in the activity of single neurons in the frontal eye fields to produce a systematic coding of smooth eye movements in three dimensional space. The utility of this coding scheme might be the functional integration of eye and hand movements by representing them in a common spatial framework. Findings: In this study, monkeys tracked targets moving in one of two planes. For frontoparallel pursuit, targets were displayed on a vertically oriented projection screen in front of the monkey. For pursuit in depth, monkeys tracked targets that were displayed on a horizontally oriented projection screen positioned at eye level, with a slight (10°) upward tilt moving away from the subject. Pursuing targets in this horizontal plane required combined frontal and vergence tracking, as targets moved both away from the subject and up, or toward the subject and down. Most neurons in the smooth pursuit region of the frontal eye fields (FEF) were driven during both frontal and vergence pursuit. Signals relating to the direction of pursuit in the two planes were independent, both in their preferred directions and their sensitivities to target speed. The activity during combined frontal and vergence pursuit when tracking targets on the horizontal plane was well predicted by the sum of these

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independent components. This linear summation could be represented by an orientation of a single preferred pursuit direction for each neuron in three-dimensional space. • Learning of sequences of finger movements and timing: frontal lobe and action-oriented representation. Sakai K, Ramnani N, Passingham RE: J Neurophysiol 2002, 88:2035-2046. Significance: This study indicates that the frontal lobe is involved in the integration of effector and timing information during learning of movement sequences. Findings: Positron emission tomography was used to determine the areas of the brain activated in three learning conditions. These conditions included: learning a sequence of finger movements with random timing, learning a sequence of timing with randomly used fingers, and learning a sequence of specific finger movements to a specific timing. Learning of a finger sequence was associated with an increment of activation in the right intraparietal sulcus and the medial parietal cortex. In contrast, learning a timing sequence was associated with an increase of activation in the lateral cerebellum and the inferior parietal lobule. Finally, the left intraparietal sulcus region, the mid-dorsolateral prefrontal cortex, and the medial and lateral premotor areas became increasingly active during learning of sequences that required both specific finger use and timing. These results suggest that frontal areas are involved in the implementation of an action oriented representation associated with the integration of the effector, and temporal information of a motor sequence.

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]

•• Role of genotype in the cycle of violence in maltreated children. Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R: Science 2002, 297:851-854. Significance: A polymorphism in the monoamine oxidase A MAOA gene may predispose children of abusive parents into becoming violent adults. Findings: A rare mutation in the sex-linked MAOA gene within a Dutch family has previously been shown to predispose males to antisocial behaviour. The enzyme MAO metabolises the neurotransmitters norepinephrine (NE), serotonin (5-HT) and dopamine (DA), and animal studies have revealed that disruptions to these transmitters in early life can lead to changes in aggressive interactions later on. In humans, a length polymorphism within the promoter of MAOA leads to changes in expression of the enzyme. More than 1000 young adults from New Zealand were genotyped for this variation, and allocated to three groups on the basis of their childhood experiences of severe, probable, or lack of maltreatment. Each subject was then given an index of antisocial behaviour that was generated according to the results from a number of psychological tests, as well as any police records. Subjects within the severe maltreatment group carrying the genotype associated with low levels of MAOA, consistently showed higher levels of antisocial behaviour, compared to those who had suffered less or no

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maltreatment, and also compared to all subjects that carried the genotype for high MAOA expression. These important results reveal the presence of a genotype–environment interaction that increases the likelihood of antisocial behaviour in young adults after they have been exposed to severe maltreatment as children, if they carry the relevant MAOA variant. • Dec1 and Dec2 are regulators of the mammalian molecular clock. Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma K-I: Nature 2002, 419:841-844. Significance: These authors have discovered another molecular loop within the mammalian circadian mechanism. Findings: The mammalian circadian machinery is directed by interlocked transcriptional/translational negative and positive feedback loops involving a number of important clock molecules. Two positive factors, BMAL1 and CLOCK, are basic helix-loophelix (bHLH) PAS proteins that activate cyclical transcription of mPer genes by binding to E-boxes on the mPer promoters. PER and particularly CRY then feedback to inhibit their own transcription, but PER may also activate bmal1 transcription, thereby interlocking the negative and positive cycles. DEC1 and DEC2 are bHLH transcription factors, and the authors were able to suppress BMAL1-CLOCK activation of an mPer promoter, either transcriptionally by directly binding to the mPer E-boxes or by binding to the N-terminal of BMAL1. Both Dec1 and Dec2 are expressed in many brain regions but are particularly enriched in the murine pacemaker, the SCN (suprachiasmatic nucleus), where their transcript abundance has a circadian cycle that peaks during the day phase. Dec1 expression was upregulated by light late at night and early in the morning, possibly via a calcium/cAMP-responsive element (CRE) in the Dec1 promoter, whereas Dec2 was unresponsive to light. The authors have unpublished data that show that BMAL1/CLOCK also upregulates Dec expression, presenting yet another example of autoregulatory feedback within the circadian mechanism, but the importance of the Dec cycle to the functioning of the clock remains to be tested via mutational analyses. • Regulation of sex-specific differentiation and mating behavior in C. elegans by a new member of the DM domain transcription factor family. Lints R, Emmons SW: Genes Dev 2002, 16:2390-2402. Significance: Identification of a new DM domain transcription factor in Caenorhabditis elegans provides additional evidence that this family of proteins are key to the generation of a sexually dimorphic nervous system. In addition, the authors suggest that DM domain genes have an ancestral function in male development. Findings: To identify genes that mediate sexual dimorphism in the C. elegans nervous system, the authors isolated mutants with defective male nervous systems. One loss-of-function mutation, called mab-23 (Male abnormal), causes defects in the differentiation of many male-specific characteristics. These include defects in the patterning of posterior sensory neurons in the male nervous system called rays, and male-specific muscle differentiation. At least one major consequence of these defects is that mab-23 mutant males are defective in male mating behaviour. The gene was cloned by the authors by genetic mapping and rescue of the mutant phenotype. mab-23 encodes a DM (Doublesex/MAB-3) domain transcription factor. To understand how mab-23 affects differentiation of the male nervous system, the authors looked at its role in ray development. These sensory neurons are believed to convey chemosensory and mechanosensory cues that are crucial to

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mating. They found that mab-23, in concert with key patterning proteins, shapes the dopaminergic identity of a given sensory neuron. The authors show that different aspects of C. elegans male sexual differentiation are coordinated among DM domain family members. Their results suggest that DM domain genes may have arisen from an ancestral male sexual regulator. • Conditional disruption of synaptic transmission induces male–male courtship behavior in Drosophila. Kitamoto T: Proc Natl Acad Sci USA 2002, 99:13232-13237. Significance: The author presents a methodology for understanding structure–function relationships in the Drosophila nervous system. This technique will be valuable in the identification of the neuronal substrates responsible for these activities, and will ultimately help to elucidate how they are incorporated into a functional behavioural circuit, in this case sexual orientation. Findings: The author had previously developed a method for studying structure–function relationships in the Drosophila nervous system (see paper alert in Curr Opin Neurobiol 2001, 11:529). The technique is reliant on a temperature-sensitive dynamin guanosine triphosphatase (GTPase) transgene. This dynamin GTPase, encoded by the Shibire gene, is essential for the recycling of synaptic vesicles. The technique allows for reversible disruption of neurotransmission in a spatially and temporally restricted manner. In this study, the author presents a strategy for exploring the structure–function relationships of distinct neuronal groups that mediate complex reproductive behaviours. Future studies will presumably concentrate on refining the functional significance of specific neuronal subsets, in particular in determining which neurons are sufficient rather than necessary for the sexual behaviour of intact animals?

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]

•• The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Saint André A, Blackwell NM, Hall LR, Hoerauf A, Brattig NW, Volkmann L, Taylor MJ, Ford L, Hise AG, Lass JH: Science 2002, 295:1892-1895. Significance: This study provides an important and rather surprising step towards a better treatment of river blindness. Findings: In a murine model of river blindness, Saint André and colleagues show that the inflammatory response was not attributable to the filarial nematodes per se — normally considered to be the pathogen responsible for river blindness — but to endosymbiotic Wolbachia bacteria. Worms that were treated with doxicyclin to eradicate Wolbachia caused less inflammation. The study not only demonstrates a new pathogenic theory for river blindness but also, somewhat ironically, suggests that treating the worms with antibiotic therapy helps the patient more than anti-filarial treatment alone. • Motoneuron death triggered by a specific pathway downstream of Fas. Potentiation by ALS-linked SOD1 mutations. Raoul C, Estevez A, Nishimune H, Cleveland D, deLapeyriere O, Henderson C, Haase G, Pettmann B: Neuron 2002, 35:1067-1083.

Significance: This study documents the interesting finding of a cell-type-specific death mechanism that might help us to understand why and how motoneurons die in Amyotrophic Lateral Sclerosis (ALS). Findings: Raoul and colleagues describe that FAS-triggered death of motoneurons, in contrast to other cell types, requires activation of a special pathway involving the upregulation of neuronal NO-synthase. In transgenic mouse models of ALS overexpressing the ALS-linked superoxide dismutase 1 mutation, the NO-synthase pathway was preferentially induced. • Subthalamic GAD gene therapy in a Parkinson’s disease rat model. Luo J, Kaplitt MG, Fitzsimons HL, Zuzga DS, Liu Y, Oshinsky ML, During MJ: Science 2002, 298:425-429. Significance: This study involves a clever yet bold experimental strategy to apply gene therapy in Parkinson’s disease (PD) by changing the output of the subthalamic nucleus (STN). Findings: In PD, the pathology in substantia nigra and striatum leads to a disinhibition of the STN. In this study, a recombinant adeno-associated virus (rAAV) gene therapy was used to essentially change the STN into an inhibitory nucleus and thus counteract the disinhibition. The approach of re-engineering the network in the basal ganglia was applied to the 6-hydroxydopamine model of PD. Although the study provokes more questions than it can answer, the central idea is very noteworthy: that the balance between excitation and inhibition in basal ganglia connections might provide a useful direct target for novel therapies in PD (and other neurodegenerative disorders). • Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Kitamura K, Yanazawa M, Sugiyama N, Miura H, Iizuka-Kogo A, Kusaka M, Omichi K, Suzuki R, Kato-Fukui Y, Kamiirisa K et al.: Nat Genetics 2002, advanced online publication: 1-11. DOI 10.1038/ng1009. Significance: This is the first report of a knockout mouse that defines a gene linked to an X-linked human cerebral malformation. It provides some important insights into neuronal proliferation, migration, and differentiation of neuroblasts during development of the embryonic forebrain. Findings: Several proteins have been associated with the appropriate glial-guided migration of neural precursor cells to the neocortex. Mutations of the encoding genes (LIS1, DCX, and RELN) result in a smooth brain (= lissencephaly) characterized by the lack of gyri and irregular thick cortex with deficient layering. The present study links mutations in the aristaless-related homeobox (Arx) gene to pedigrees with males identified by a severe lissencephaly and ambiguous genitalia. Male embryonic mice with Arx mutations show important characteristics of this human disorder with microcephaly, suppressed proliferation, and aberrant migration of GABAergic interneurons, as well as abnormal testicular differentiation. • Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Wilson SM, Bhattacharyya B, Rachel RA, Coppola V, Tessarollo L, Householder DB, Fletcher CF, Miller RJ, Copeland NG, Jenkins NA: Nat Genetics 2002, advanced online publication: 1-6. DOI 10.1038/ng1006. Significance: This study employs an interesting genetic approach to reveal that ubiquitin proteases processing polyubiquitin, a protein associated with aggregates in Parkinson’s

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disease and spinocerebellar ataxia type 1, may play an important role in regulating synaptic transmission. Findings: Mice with a homozygous mutation in the ataxia gene (axj) show clinical deficits such as severe tremors and hindlimb paralysis shortly followed by death. This gene encodes an ubiquitin-specific protease 14 (Usp14) that specifically cleaves ubiquitin conjugates. In contrast to the human counterparts, no protein aggregates or neuronal cell loss was detected in axj mice, instead dysfunctional synaptic transmission measured by paired pulse facilitation was detected in hippocampal circuits. •• Regeneration of hippocampal neurons after ischemic brain injury by recruitment of endogenous neural progenitors.

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Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M: Cell 2002, 110:429-441. Significance: This study uses a very effective and novel approach to endogenous neuronal cell regeneration for stroke leading to substantial morphological and functional recovery. Findings: For the first time, this study shows convincingly a growth factor (EGF and FGF-2)-mediated stimulation of endogenous progenitor cells that are capable of migration from the most potent neurogenic region of the subventricular zone into the ischemic hippocampus. After arrival in the lesioned area, these newborn cells differentiate and integrate into existing hippocampal circuitry, thereby leading to an improvement in spatial memory.