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. Current Opinion in Neurobiology 2000, 10:661–670 Contents (chosen by) 661 Development (Lumsden et al.) 662 Cognitive neuroscience (Mayford, Hamann and Reber) 664 Signalling mechanisms (Häusser and Murthy) 665 Sensory systems (Wood and Liman) 666 Neuronal and glial cell biology (Sheng) 667 Motor systems (Ashe and Chafee) 667 Neurobiology of behaviour (Goodwin and Kyriacou) 669 Neurobiology of disease (Kempermann and Winkler) 670 Corrigendum (Goodwin and Kyriacou) • ••
of special interest of outstanding interest
Development Selected by Andrew Lumsden, Monica Ensini, Jon Gilthorpe, Frank R Schubert, Michèle Studer, Leah Toole King’s College London, Guy’s Hospital, London, UK
Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Litingtung Y, Chiang C. Nat Neurosci 2000, 3:979-985. •• Significance: Although signalling by Sonic hedgehog from ventral midline tissues has been considered necessary for motor neuron induction and patterning, this paper shows that other signalling pathways can perform these functions. Findings: Specification of distinct neuronal types in the ventral spinal cord has been thought to depend on graded Sonic hedgehog (Shh) signalling from the ventral midline, floor plate and notochord; Shh–/– embryos lack motor neurons, for example. However, mouse embryos which are null mutant for both Shh and one of its downstream targets, Gli3, develop most ventral cell types, including motor neurons, in a near-normal pattern. This finding suggests that Shh normally antagonizes Gli3-mediated repression of ventral spinal cord patterning and that this event would require additional factors distinct from Shh, such as retinoic acid. A pre-pattern established by such factors may be subsequently reinforced and refined by Shh signalling. Genetic and epigenetic mechanisms contribute to motor neuron pathfinding. Sharma K, Leonard AE, Lettieri K, Pfaff SL: Nature 2000, 406:515-519. AND
Coordinate roles for LIM homeobox genes in directing the dorsoventral trajectory of the motor axons in the vertebrate limb. Kania A, Johnson RL, Jessell TM: Cell 2000, 102:161-173. • Significance: These two papers show that LIM homeodomain transcription factors seem to play an important role in regulating cell migration and axon pathfinding by spinal motor neurons. Findings: Sharma et al. produced a mouse transgenic line in which all motor neurons were forced to ectopically express a
LIM gene combination typical of the subgroup innervating axial muscles. This genetic alteration is sufficient to force motor neurons to acquire an axial identity in terms of cell body settling pattern, gene expression profile and axonal projections. Nevertheless, epigenetic factors can override their genetic program, causing some axons to project to alternative targets. Kania et al. show that two LIM homeodomain transcription factors, Lim1 (expressed by a set of lateral motor column neurons) and Lmx1b (expressed by dorsal limb mesenchymal cells), control the initial trajectory of motor axons in the developing mammalian limb. In the absence of these two factors, motor axons appear to select dorsal and ventral trajectories at random, suggesting that LIM homeodomain proteins act to establish the fidelity of a binary choice in axonal trajectory. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Wehrli M, Dougan ST, Caldwell K, O’Keefe L, Schwartz S, Vaizel-Ohayon D, Schejter E, Tomlinson A, DiNardo S: Nature 2000, 407:527-530. AND
LDL-receptor-related proteins in Wnt signal transduction. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X: Nature 2000, 407:530-535. AND
An LDL-receptor-related protein mediates Wnt signalling in mice. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC: Nature 2000, 407:535-538. • Significance: These three papers ascribe a new and evolutionarily conserved role of a subfamily of the low-density lipoprotein (LDL)-receptor-related protein (LRP) family, LRP5 and LRP6, as co-receptors in the Wnt signal transduction pathway. Findings: Mainly implicated in the transport of lipoproteins into the cell, members of the LDL receptor family also play a role in specific signalling pathways during development. In the absence of VLDL (very low-density lipoprotein) and ApoER2 (ApoE receptor 2) receptors, mutant mice phenocopy a Reeler/Disabled-like disruption of neuronal migration. Here, a combination of genetic, molecular and biochemical experiments in three animal models demonstrates a central role for the mammalian LRP5 and LRP6 receptors and their Drosophila orthologue arrow in cells receiving wingless/Wnt signals. Functional studies in Drosophila and Xenopus show that arrow and LRP6 can specifically activate wingless/Wnt signalling by functioning upstream of the intracellular protein Dishevelled (Dsh) and the β-catenin pathway. Various biochemical approaches show that LRP6 can bind Wnt1 and form a complex with its cognate receptor Frizzled (Fz) in a Wnt-dependent fashion, strongly suggesting that LRP6 is a component of the Wnt–Fz receptor complex. In the Drosophila embryo, arrow function is required for all wingless-dependent patterning events, whereas truncated forms of the LRP6 protein in Xenopus and LRP6 mutant mice do not display all of the Wnt phenotypes reported to date and have less severe defects than those exhibited by individual Wnt mutants. Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons. Bhatt RS, Tomoda T, Fang Y, Hatten ME: Genes Dev 2000, 14:2216-2228.
• Significance: Reveals a novel role for discoidin domain receptor 1 (DDR1) in granule cell axon outgrowth in the cerebellum. It is likely that pial-derived collagen signals through DDR1 to cause parallel fibre extension. Findings: Within the cerebellum, collagen is localized in a concentration gradient that is highest at the pial surface and declines toward the ventricular surface. Collagen appears to signal via DDR1 to cause granule cell neurite extension. Overexpression of a dominant-negative form of DDR1 in immature granule cells results in disrupted axon extension of parallel fibres in vivo, in primary culture and in organotypic cerebellar slices. Furthermore, the use of proliferation and differentiation markers reveals that granule cell axon extension is blocked after cells commit to terminal differentiation. The Drosophila Netrin receptor Frazzled guides axons by controlling Netrin distribution. Hiramoto M, Hiromi Y, Giniger E, Hotta Y: Nature 2000, 406:886-889. • Significance: In addition to the conventional role of the Netrin receptor in signal transduction, the authors assign it a surprising, novel function in ligand distribution and presentation. Findings: Two puzzling findings indicate an unexpected role for the Netrin receptor Frazzled in Drosophila: Frazzled acts noncell-autonomously in photoreceptor axon guidance, and Netrin protein is distributed like Frazzled, but unlike its own mRNA. Using ectopic expression of wild-type and mutant Frazzled, Hiramato et al. show that Frazzled is sufficient to rearrange Netrin protein distribution. This function depends on the extracellular domain of Frazzled, while the cytoplasmic domain determines the intracellular distribution of Frazzled protein.
Cognitive neuroscience Selected by Mark Mayford University of California—San Diego, La Jolla, California, USA
Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nader K, Schafe GE, LeDoux JE: Nature 2000, 406:722-726. •• Significance: This study presents strong evidence that fear memories show increased lability during recall. The results suggest that the act of recall, rather than simply reactivating a memory trace, recruits an active molecular mechanism that is required for the memory to remain stably stored. Findings: Rats were trained in a fear conditioning task in which a tone-CS (conditioned stimulus) is repeatedly paired with a mild foot-shock-US (unconditioned stimulus) such that the rats learn to fear the tone. This memory requires the amygdala and is robust even during multiple recall tests. However, if a protein synthesis inhibitor is infused into the amygdala during a recall test, the memory is disrupted. Impaired synaptic plasticity and cAMP response elementbinding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice. Ho N, Liauw JA, Blaeser F, Wei F, Hanissian S, Muglia LM, Wozniak DF, Nardi A, Arvin KL, Holtzman DM: J Neurosci 2000, 20:6459-6472. •• Significance: Neuronal-activity-induced genes, such as cFos, are thought to play a role in synaptic plasticity and memory. The results suggest that induction of these genes may not be necessary for memory formation. Findings: CaMKIV is a Ca2+/calmodulin-dependent protein kinase that has been implicated in neuronal-activity-induced gene expression. A mouse carrying a null mutation in CaMKIV was generated. The knockout mouse showed impaired induction
of CREB (cAMP-response-element binding protein) phosphorylation, c-Fos expression, and hippocampal LTP. However, spatial memory appeared normal. Good memories of bad events in infancy. Sullivan RM, Landers M, Yeaman B, Wilson DA: Nature 2000, 407:38-39. • Significance: The authors demonstrate that a negative reinforcer such as a shock can act as a positive reinforcer in early post-natal rat pups. This may represent a model of attachment to an abusive care-giver. Findings: Rat pups were trained in a simple olfactory avoidance task in which a discrete odor cue was paired with a mild aversive shock. Surprisingly, pups trained at post-natal day 9 showed an increased preference for the conditioned odor. Pups trained at post-natal day 10 and beyond showed the expected aversion to the conditioned odor. Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Iwasato T, Datwani A, Wolf AM, Nishiyama H, Taguchi Y, Tonegawa S, Knopfel T, Erzurumlu RS, Itohara S: Nature 2000, 406:726-731. • Significance: This is the clearest demonstration to date of a role for NMDA receptor function in developmental plasticity in the neocortex. Findings: Transgenic mice were generated in which the NMDA receptor was deleted specifically in excitatory neurons of the cortex at an early developmental stage. Somatotopic patterning of the barrel cortex, although still present, was clearly disrupted. Selected by Stephan Hamann Emory University, Atlanta, Georgia, USA
Replaying the game: hypnagogic images in normals and amnesics. Stickgold R, Malia A, Maguire D, Roddenberry D, O’Connor M: Science 2000, 290:350-353. • Significance: This study provides new insight into the type of memory that is involved in creating dreams and how material from waking life is incorporated into dreams. Findings: This study examined hypnagogic imagery, spontaneous images that are experienced as one begins to fall asleep. The primary issue concerned the way in which recent visual experience affects these images and whether such images depend on the declarative memory system — the hippocampalbased system that mediates memory for conscious remembering of facts and events. Subjects received extensive exposure over three days to a computer game that involved fitting falling colored shapes into one another. Subjects were tested by being asked to self-report the contents of their hypnogogic imagery. Most subjects reported seeing stereotyped hypnagogic imagery related to the game, such falling blocks, but the onset of this imagery was delayed until 24 h after the beginning of game exposure. Critically, amnesic patients who were severely impaired in remembering new experiences were also tested. The incidence and quality of the stereotyped game images was similar for the amnesic patients and the healthy controls. This suggests that although hypnagogic images reflect recent experience and are thus a form of memory, this form of memory is distinct from the declarative memories that are impaired in amnesia. The authors speculate that if hypnagogic imagery is representative of dreams in general, the lack of hippocampal involvement in image generation may help to explain the bizarreness of dreams, as the hippocampal system is necessary for maintaining the correct temporal and spatial orientation of elements in memory. In addition, the blockage of
the hippocampal system may unmask weak cortical connections between memories, which could account for the often irrational connections which are characteristic of dreams. Functional magnetic resonance imaging (fMRI) activity in the hippocampal region during recognition memory. Stark CEL, Squire LR: J Neurosci 2000, 20:7776-7781. • Significance: The authors demonstrate that the human hippocampus is active during recognition of previously exposed words and pictures, clarifying the role of the hippocampus in recognition memory and providing an important link to prior neuropsychological and animal studies which indicated that the hippocampus is critical for recognition memory. Findings: Although human and animal lesion studies have supported a critical role for the hippocampus in declarative memory for facts and events, neuroimaging studies have often failed to find hippocampal activation during memory retrieval. This study examined activity in the hippocampal region during a recognition memory test in which words and pictures were presented and subjects asked to decide which of these items had been presented in an earlier study list. The question of interest was whether memory retrieval in a recognition memory test would be accompanied by hippocampal activation. The motivation for this question was to test a recently proposed theory (Aggleton JP, Brown MW: Behav Brain Sci 1999, 22:425-428) about the memory functions of the medial temporal lobe. It has been proposed that associative memory functions, such as the formation of an association between two objects, are mediated by the hippocampus, whereas familiarity — the simple knowledge that something has been previously experienced — is mediated by the cortex adjacent to the hippocampus. This theory predicts that recognition of single items should not involve hippocampal activity because this memory task can be performed using familiarity alone, without the need for associative processes. Previous studies that successfully observed hippocampal activity during recognition memory retrieval had all used procedures which involved overtly associative processes. This study simply presented words or pictures during a study phase and then scanned brain activity using fMRI during a retrieval test in which blocks of old or new items were presented and subjects asked to make judgments about whether the items were old or new. Regions of interest were defined around the hippocampal formation bilaterally and the number of pixels achieving a set statistical threshold was counted and averaged across a group of subjects. Recognition for words and pictures produced robust activation of the left hippocampus. Right hippocampal activity was also detected but only for the picture stimuli, consistent with the lateralization of the additional, nonverbal information contained in the pictures. The theory that recognition memory for single items would not involve hippocampal activation was not supported. The authors conclude that the hippocampus is necessary not only for overtly associative forms of memory, but also for the simple recognition that an item has been previously presented. This finding accords well with neuropsychological studies of patients with selective hippocampal damage, who show clear deficits in recognition memory. Selected by Paul J Reber Northwestern University, Evanston, Illinois, USA
Patterns of brain activation in people at risk for Alzheimer’s disease. Bookheimer SY, Strojwas MJ, Cohen MS, Saunders AM, Pericak-Vance MA, Mazziota JC, Small GW: N Engl J Med 2000, 343:450-456.
•• Significance: This is the first report to use functional magnetic resonance imaging (fMRI) as a tool for assessing memory function in order to predict memory decline in patients at high risk for developing Alzheimer’s disease. Findings: Memory function was compared in patients who were identified as carriers of the apoliprotein E gene (APOE) e4 allele, a risk factor for subsequent development of Alzheimer’s disease, as well as a control group of participants with the APOE e3 allele. Participants performed both a study and retrieval task while brain activity levels were assessed throughout the brain using fMRI. The extent of activation was greater in the patients with the APOE e4 allele although retrieval performance was worse, suggesting that more neural effort was required by this group in order to perform the memory tasks. This result indicates that incipient memory dysfunction may be detectable at an earlier stage by use of fMRI assessments than by use of structural assessments of neuropathology or behavioral measures. Hippocampal neurons encode information about different types of memory episodes occurring in the same location. Wood ER, Dudchenko PA, Robitsek RJ, Eichenbaum H: Neuron 2000, 27:623-633. • Significance: Electrophysiological evidence from the rat hippocampus indicates the existence of cells whose firing properties appear to be primarily mnemonic rather than spatial in nature. This provides evidence that the rat hippocampus plays an important role in memory as well as spatial functions. Findings: This report addresses a long-standing debate on the role of the hippocampus in spatial and memory function. Although the hippocampus is strongly associated with memory function in humans, electrophysiological recordings in rats have documented firing patterns that are dependent on spatial position, orientation and movement. The current study reports electrophysiological activity in the rat that is dependent on the memory aspects of a spatial alternation task and that could not be attributed to running speed or heading. This provides clear electrophysiological evidence of the memory functions of the rat hippocampus that are additional to the spatial functions of this brain area. Domain specificity in face perception. Kanwisher N: Nat Neurosci 2000, 4:759-763. AND
FFA: a flexible fusiform area for subordinate-level visual processing automatized by expertise. Tarr M, Gauthier I: Nat Neurosci 2000, 3:764-769. • Significance: The neural substrate of high-level visual cognition is located in an area in which current theoretical debates have implications as far-reaching as the nature/nurture dilemma facing learning, cognition and development. Central to the current issue is the function of an area of the temporal lobe that is hypothesized to be specialized for face perception, the fusiform face area (FFA) that has been described in the paper by Kanwisher. Findings: Studies of prosopagnosic patients (i.e. patients with a selective deficit in perceiving faces) and functional neuroimaging studies both suggest that there is an area of the brain specialized for perceiving faces. However, this recent study by Tarr and Gauthier suggests an alternate hypothesis: that the FFA is an area specialized for making fine, expert discriminations among similar objects within a category and that face recognition is just an example of this more general process. The elements of this debate reflect the use of increasingly sophisticated neuroscience techniques for both brain
imaging and neuropsychology. The characteristics and emergence of these high-level visual processing areas, whether domain-specific or domain-general, are of particular relevance to the field of cognitive neuroscience as a whole.
Signalling mechanisms Selected by Michael Häusser University College London, London, UK
Molecular and neuronal substrate for the selective attenuation of anxiety. Low K, Crestani F, Keist R, Benke D, Brunig I, Benson JA, Fritschy JM, Rulicke T, Bluethmann H, Mohler H: Science 2000, 290:131-134. •• Significance: The authors identify the α2 GABAA receptor subtype as that responsible for the attenuation of anxiety by benzodiazepine tranquilizers such as diazepam. This designates the α2 receptor as a highly specific target for the development of new anxiolytic drugs. Findings: The authors generated transgenic mice in which the α2 or α3 GABAA receptors were rendered insensitive to diazepam by a knock-in point mutation. Only the mice with the α2 point mutation were insensitive to the anxiolytic action of diazepam. As the α2-containing receptors have a distinctive expression pattern, being particularly abundant in the limbic system and on the initial segment of pyramidal cell axons in cortex, this finding also points to the possible neural mechanisms involved in suppressing anxiety. Active stabilization of electrodes for intracellular recording in awake behaving animals. Fee MS: Neuron 2000, 27:461-468. • Significance: The author describes a technological breakthrough that enables stable intracellular recordings to be made from neurons in awake active animals. This novel technique will facilitate advances in our understanding of the contribution of single neurons and synaptic dynamics to behaviour. Findings: The pulsations associated with respiration, heartbeat and movement in intact behaving animals have previously made intracellular recordings virtually impossible. The author recorded physiological signals that are strongly correlated with brain movement, such as the electrocardiogram, respiratory pressure, or cranial motion, and used these signals to control electrode position via a piezoelectric micromanipulator. Intracellular recordings from the sensorimotor cortex of rats running on a treadmill are used to demonstrate the effectiveness of the method. Selected by Venkatesh N Murthy Harvard University, Cambridge, Massachusetts, USA
Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Bellochio EE, Reimer RJ, Fremeau RT Jr, Edwards RH: Science 2000, 289:957-960. AND
Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons. Takamori S, Rhee JS, Rosenmund C, Jahn R: Nature 2000, 407:189-194. •• Significance: A large fraction of neurons in the vertebrate brain use glutamate stored in synaptic vesicles for neurotransmission. The identity of the protein(s) responsible for transporting glutamate into vesicles has remained unknown. Now, two groups report the cloning and characterization of a vesicular glutamate transporter. Findings: On the basis of circumstantial evidence, the authors of the first paper suspected that the brain-specific Na+-dependent
inorganic phosphate transporter (BNPI) might also play a role in transporting glutamate. Vesicles isolated from PC12 cells expressing this protein were able to transport 3H-labeled glutamate. In the second paper, the authors used gel electrophoresis to separate proteins present on purified synaptic vesicles, and identified BNPI as a vesicular protein. Vesicles immunopurified using antibodies against BNPI could transport glutamate, and cell lines expressing this protein exhibited glutamate uptake. Both reports find that glutamate uptake mediated by BNPI depends on the electrical component of the electrochemical gradient. Takamori et al. also describe elegant electrophysiological experiments in which glutamate release from a cell line expressing BNPI was detected using neuronal glutamate receptors expressed in HEK cells. Finally, they also report that expressing BNPI in GABAergic hippocampal neurons causes them to release glutamate in addition to GABA. Somatic EPSP amplitude is independent of synapse location in hippocampal pyramidal neurons. Magee JC, Cook EP: Nat Neurosci 2000, 3:895-903. • Significance: This is the first direct demonstration that synapses from distal and proximal regions of the dendritic tree can have equal influence on action potential generation. The authors make the surprising observation that the strength of synapses made on hippocampal neurons in the CA1 region increases as a function of distance from the soma, compensating for the normal attenuation expected from cable theory. Findings: Synapses made further away from the cell body of neurons will be more attenuated than those made proximally as a result of the leakiness of cell membranes. Recently, many proposals involving active currents of one sort or another have been proposed to offset such attenuation. In this study, the authors use the difficult method of recording simultaneously from a somatic and a dendritic location of a single neuron to show that the intrinsic strength of the synapse increases as one proceeds away from the soma. Unitary synaptic currents evoked by local application of hyperosmotic solution on different regions of the dendritic tree were of similar amplitudes when recorded at the soma. Local recordings in the dendrite, however, revealed that synapses further from the soma had larger unitary amplitudes. Careful control experiments revealed that this increased amplitude was a result of larger synaptic conductance. Presenilin-mediated modulation of capacitive calcium entry. Yoo AS, Cheng I, Chung S, Grenfell TZ, Lee H, Pack-Chung E, Handler M, Shen J, Xia W, Tesco G et al.: Neuron 2000, 27:561-572. • Significance: Recently, it has become apparent that presenilins (PS1 and PS2), proteins whose mutations are associated with a familial form of Alzheimer’s disease, are involved in calcium homeostasis in cells. This paper provides direct cell-biological evidence that presenilin-1 plays a role in a form of Ca2+ entry into neurons that might be important for maintaining appropriate Ca2+ levels in the endoplasmic reticulum. Findings: In most cells, when Ca2+ stores are depleted by signaling events, store-operated Ca2+ channels open and cause Ca2+ influx into the cell. This entry, termed capacitative Ca2+ entry, is potentiated in cortical neurons lacking PS1. In contrast, it is attenuated in cells expressing a familial Alzhemier’s-disease-linked mutant form of PS1 or PS2. Interestingly, the authors find that the formation of the amyloid peptide Aβ42 is enhanced when capacitative Ca2+ entry is inhibited in HEK or CHO cell lines. In contrast, increasing the levels of Aβ42 either
directly or through overexpression of amyloid precursor protein does not alter capacitative Ca2+ entry. This suggests that impairment of capacitative Ca2+ entry in mutant PS1 cells is upstream of Aβ42 increase.
Sensory systems Selected by John N Wood University College London, UK
Positive and negative interactions of GDNF, NTN and ART in developing sensory neuron subpopulations, and their collaboration with neurotrophins. Baudet C, Mikaels A, Westphal H, Johansen J, Johansen TE, Ernfors P: Development 2000, 127:4335-4344. AND
Potent analgesic effects of GDNF in neuropathic pain states. Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN, McMahon SB: Science 2000, 290:124-127. •• Significance: In the first paper, the trophic actions of members of the glial-cell-line-derived neurotrophic factor (GDNF) family of ligands on the survival of subpopulations of sensory neurons are comprehensively examined. In the second paper, a useful pharmacological action of high-dose GDNF administration in the treatment of neuropathic pain (pain resulting from damage to peripheral sensory neurons) in adult animals is described. A possible mechanism for this analgesic action, which involves the regulation of expression of sodium channel subtypes that underlie ectopic action potential propagation after nerve injury, is described. Findings: GDNF, neurturin (NTN) and neublastin/artemin (ART) elicit neurotrophic effects on subsets of peripheral and central neurons. Embryonic dorsal root ganglion (DRG) sensory neurons express GDNF receptors but do not survive in response to the ligands until the postnatal period. GDNF and NTN support distinct neural subpopulations, whereas ART supports neurons in populations that are also responsive to GDNF or NTN. Sensory neurons that coexpress GDNF-family receptors are medium sized, whereas small nociceptive cells preferentially express a single trophic factor receptor. Neurotrophin-3- (NT3-) or -4 (NT4-) dependent neurons, including proprioceptive afferents, Merkel end organs and D-hair afferents, are also supported by GDNF-family ligands neonatally, although at postnatal stages they lose their dependency on GDNF and NTN. At late postnatal stages, ART prevents survival elicited by GDNF and NTN. In adult animals, GDNF has interesting effects on the development of neuropathic pain. GDNF both prevents and reverses sensory abnormalities that develop in neuropathic pain models in rats, without affecting pain-related behavior in normal animals. GDNF reduces ectopic electrical discharges within sensory neurons after nerve injury and normalises the expression of sodium channel transcripts — in particular, downregulating the expression of the type III sodium channel which may be involved in hyperexcitability in damaged nerves. This suggests that GDNF may provide a therapeutic treatment for neuropathic pain states. Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. Black JA, Dib-Hajj S, Baker D, Newcombe J, Cuzner ML, Waxman SG: Proc Natl Acad Sci USA 2000, 97:11598-11602. • Significance: An altered pattern of sodium channel expression in multiple sclerosis is demonstrated here, suggesting that
some aspects of the pathology of the disease may result from changes in the excitability of central neurons. Findings: Multiple sclerosis (MS) has been considered to be caused by demyelination and/or axonal degeneration, and little attention has been paid to other changes in neuronal properties associated with this condition. However, the sensory-neuronspecific (SNS) sodium channel mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS known as chronic relapsing experimental allergic encephalomyelitis. SNS mRNA and protein expression within Purkinje cells has also been demonstrated in tissue samples obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia in these disorders. Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity. Holmes FE, Mahoney S, King VR, Bacon A, Kerr NC, Pachnis V, Curtis R, Priestley JV, Wynick D: Proc Natl Acad Sci USA 2000, 97:11563-11568. AND
Galanin regulates the postnatal survival of a subset of basal forebrain cholinergic neurons. O’Meara G, Coumis U, Ma SY, Kehr J, Mahoney S, Bacon A, Allen SJ, Holmes F, Kahl U, Wang FH et al.: Proc Natl Acad Sci USA 2000, 97:11569-11574. •• Significance: Galanin is a neuropeptide with various actions on central and peripheral neurons. Using galanin-null mutant mice, a trophic action of galanin on both peripheral and central neuronal survival has been discovered. Findings: Adult galanin-null mutant mice have a 13% reduction in the number of cells in the dorsal root ganglion (DRG), associated with a 24% decrease in the percentage of neurons that express substance P. After crush injury to the sciatic nerve, the rate of peripheral nerve regeneration is reduced by 35% with associated long-term functional deficits. Cultured DRG neurons from adult mutant mice demonstrate similar deficits in neurite number and length. These results identify a critical role for galanin in the development and regeneration of sensory neurons. In the central nervous system, galanin colocalizes with choline acetyltransferase in a subset of cholinergic neurons in the basal forebrain of rodents. A third of cholinergic neurons in the medial septum and vertical limb diagonal band of the basal forebrain of adult mice are also lost in the galanin-null mutant. This loss is associated with marked age-dependent deficits in stimulated acetylcholine release, performance in the Morris water maze, and induction of long-term potentiation in the CA1 region of the hippocampus. These results provide strong evidence of an important trophic role for galanin within both peripheral and central nervous sytems. Mechanosensitive potassium channels in rat colon sensory neurons. Su X, Wachtel RE, Gebhart GF: J Neurophysiol 2000, 84:836-843. •• Significance: The mechanisms involved in transducing mechanical stimuli are little understood in vertebrates. A K+-selective ion channel in colon sensory neurons has been found to be activated by pressure, and its single channel properties characterised. Findings: DiI-labelled colon sensory neurons were isolated from adult rat dorsal root ganglia, and patches analysed for the
expression of mechanosensitive currents. Channels were highly selective for K+, had a slope conductance of 54 pS in symmetrical solutions, and were blocked by tetraethylammonium, amiloride and benzamil, but not gadolinium, tetrodotoxin or 4-aminopyridine. Channel activity was also seen under Ca2+free conditions. The cytoskeletal disrupters colchicine and cytochalasin D reduced the percentage of patches containing mechanosensitive channels. Thus, rat colon sensory neurons contain K+-selective mechanosensitive channels that may modulate the membrane excitability induced by colonic distension. Selected by Emily R Liman University of Southern California, Los Angles, CA, USA
Ultrasensitive pheromone detection by mammalian vomeronasal neurons. Leinders-Zufall T, Lane AP, Puche AC, Ma W, Novotny MV, Shipley MT, Zufall F: Nature 2000, 405:792-796. •• Significance: This paper reports the remarkable discovery that vomeronasal sensory neurons (VSNs) respond to extremely low concentrations of pheromones with extraordinary specificity. Findings: Using three different methods — extracellular recording, loose-patch recording and Ca2+ imaging — the authors examine the responses of mouse VSNs to six chemicals known to be pheromones. These chemicals are released by mice, primarily in urine, and have been shown to alter the behavioral or neuroendocrine response of the recipient animal. Remarkably, at concentrations of 10—10–10–11 M, all six pheromones were effective at eliciting field potentials across the vomeronasal epithelium, and at eliciting action potentials and increases in intracellular Ca2+ in a small percentage of cells. Furthermore, VSNs were highly tuned for specific pheromones, and higher concentrations of pheromones did not recruit greater numbers of responsive cells. These results are consistent with the notion that sensory receptors and pheromones have co-evolved, allowing for a form of chemical communication that is highly specific and stereotyped. Responses of vomeronasal neurons to natural stimuli. Holy TE, Dulac C, Meister M: Science 2000, 289:1569-1572. •• Significance: Using a multi-electrode array, these authors have been able to demonstrate robust electrophysiological responses to pheromone-containing substances by vomeronasal sensory neurons. This technology has allowed the authors to begin to characterize sensory transduction in the vomeronasal system. Findings: The authors have tackled the challenge of recording sensory responses from vomeronasal sensory neurons (VSNs) by using a 64-electrode microarray that is placed underneath the epithelium. They demonstrate that they can elicit action potentials from VSNs with a substance known to contain pheromones — dilute urine — and that the action potentials result from activation of a sensory transduction cascade. The responses are blocked by an inhibitor of phospholipase C (PLC), consistent with previous suggestions that a PLC signaling cascade mediates vomeronasal sensory transduction. The authors further demonstrate that the sensory response is nonadapting, allowing VSNs to improve sensitivity through temporal integration. Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Wong ST, Trinh K, Hacker B, Chan GCK, Lowe G, Gaggar A, Xia Z, Gold GH, Storm DR: Neuron 2000, 27:487-497.
• Significance: Olfactory sensory transduction is known to involve generation of the second messenger cAMP. This paper identifies adenylyl cyclase (AC) type III as the enzyme underlying the olfactory sensory response. Findings: Odorants are transduced in the olfactory epithelium through a cyclic-nucleotide signaling pathway that involves activation of an AC and culminates in the opening of cyclic-nucleotide-gated ion channels. An alternative pathway involving IP3 has also been proposed. These authors created a targeted disruption of type III AC and examined the consequence for sensory transduction and olfactory-guided behaviors. AC III knockout mice showed no sensory response to odorants, as measured by extracellular recording, nor did they show any behavioral response to odorants, as measured by two tests of olfactory learning. These results firmly demonstrate that AC III is an essential component of olfactory sensory transduction.
Neuronal and glial cell biology Selected by Morgan Sheng Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA
Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. Chung HJ, Xia J, Scannevin RH, Zhang X, Huganir RL: J Neurosci 2000, 20:7258-7267. • Significance: The trafficking of AMPA receptors at postsynaptic sites plays an important role in synaptic plasticity and is likely to be regulated by receptor interactions with PDZ-domain scaffold proteins. This study characterizes phosphorylation of a serine residue (serine-880) in the carboxy-terminal tail of the GluR2 subunit that is critical for PDZ-domain binding. Phosphorylation of this residue can potentially switch GluR2 binding from one PDZ protein (glutamate-receptor-interacting protein, GRIP) to another (protein interacting with Cα kinase 1, PICK1). Findings: Phosphorylation of GluR2 serine-880 (detected by a phospho-specific antibody) occurs in vivo and is increased by stimulation with phorbol ester. Serine-880 phosphorylation prevents GluR2 binding to GRIP but not to PICK1. In cultured hippocampal neurons, phorbol ester stimulates AMPA receptor internalization, which is accompanied by increased staining for serine-880-phosphorylated GluR2 and PICK1 in dendritic spines. TRP and the PDZ protein, INAD, form the core complex required for retention of the signalplex in Drosophila photoreceptor cells. Li HS, Montell C: J Cell Biol 2000, 150:1411-1421. • Significance: Drosophila INAD (inactivation no afterdepolarization) is a multi-PDZ-domain scaffold protein that assembles components of the G-protein-coupled phototransduction cascade into a large signaling complex. INAD-interacting proteins such as protein kinase C, phospholipase C, and the light-activated channel TRP (transient receptor potential) depend on INAD for their localization in rhabdomeres (the phototransduction centers of Drosophila photoreceptor cells). However, the way in which INAD itself is targeted to the rhabdomere was previously unknown. This paper demonstrates that INAD and TRP are mutually dependent for their localization in rhabdomeres. Thus the INAD–TRP interaction may form the axis that is critical for assembly and localization of the phototransduction complex. Findings: In trp mutant flies, INAD itself and other molecules that are dependent on INAD for their localization to the rhabdomeres are mislocalized. The direct binding between TRP and INAD is mediated by the carboxyl terminus of TRP and a PDZ
domain of INAD. Early in development, rhabdomere localization of TRP is not fully dependent on INAD. Molecular memory by reversible translocation of calcium/calmodulin-dependent protein kinase II. Shen K, Teruel MN, Connor JH, Shenolikar S, Meyer T: Nat Neurosci 2000, 3:881-886. • Significance: Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of synaptic plasticity. This paper demonstrates that synaptic stimulation that induces long-term potentiation causes CaMKII to become persistently translocated to synapses (‘trapped’). The prolonged localization of CaMKII near its substrates may serve as a biochemical ‘memory’ of an activated synapse. Findings: Hippocampal neurons were transfected with green fluorescent protein (GFP)-tagged CaMKII and monitored by real-time confocal microscopy. Electrical or glutamate stimulation caused GFP–CaMKII to translocate to synapses for periods (half-life of 200–300 s) much longer than the stimulus itself. Trapping required CaMKII autophosphorylation and was regulated by protein phosphatase 1/protein kinase A. After dissociation from postsynaptic targets, cytosolic CaMKII remained temporarily in a ‘primed’ state that could undergo facilitated translocation to synapses. Glutamate receptors regulate actin-based plasticity in dendritic spines. Fischer M, Kaech S, Wagner U, Brinkhaus H, Matus A: Nat Neurosci 2000, 3:887-894. • Significance: Dendritic spines exhibit rapid actin-dependent motility, but the relationship between spine shape/motility and synaptic function is not well understood. This study reveals that activation of AMPA receptors inhibits spine motility, consistent with a role for AMPA receptors in stabilizing the morphology of dendritic spines. Findings: Dendritic spine motility was visualized by time-lapse imaging of hippocampal neurons expressing GFP-tagged actin. Application of AMPA (at a concentration as low as 1 mM) rapidly and reversibly inhibited spine motility and induced a more rounded spine shape. The AMPA effect required membrane depolarization and was mediated at least in part by low-voltage-activated Ca2+ channels.
Motor systems Selected by James Ashe and Matthew Chafee Brain Sciences Center, VAMC, Minneapolis, Minnesota, USA
Corticostriatal activity in primary motor cortex of the macaque. Turner RS, DeLong MR: J Neurosci 2000, 20:7096-7108. • Significance: This study indicates that motor cortex provides an output to the striatum that is functionally as well as anatomically distinct from the output it provides to the spinal cord. This offers insight both into the types of signal transmitted through the basal ganglia and the functional significance this flow of activity might have for motor performance. Findings: The authors were able to distinguish between neurons in primary motor cortex that project to the striatum from those that project to the spinal cord and brain stem by use of antidromic stimulation (stimulating electrodes were placed either in arm-responsive regions of the striatum or the prepontine cerebral peduncle). Corticostriatal neurons had lower firing rates and slower conduction velocities, and were much less frequently driven by somatosensory stimulation. Fewer corticostriatal neurons exhibited activity modulation during
movement, which when present was less intense, and less frequently exhibited a muscle-like response to torque loads (e.g. firing at higher rates when movements were opposed and more force required). Of those corticostriatal cells that were active during movement, a greater proportion exhibited purely directional movement signals. Precise spatiotemporal repeating patterns in monkey primary and supplementary motor areas occur at chance levels. Baker SN, Lemon RN: J Neurophysiol 2000, 84:1770-1780. •• Significance: It has been proposed that precisely repeating patterns of spikes in cortical neurons encode information in the brain. Although repeating spike patterns exist, it is possible that these are generated by a random process and so represent chance events. This study reports that the number of repeating spike patterns observed in cortical neurons does not exceed the number observed in randomly generated data. This is evidence against the theory that repeating spike patterns constitute a temporal code. Findings: A comparison was made between the number and complexity of repeating spike patterns detected in spike trains recorded from neurons in the motor and supplementary motor cortex, and surrogate spike trains generated by a Poisson process. Surrogate trains closely paralleled the fluctuation in firing rate present in the original data, contained a nearly identical distribution of interspike intervals, but destroyed any finer temporal structure present in the exact timing of spikes, being generated by a random process. Although very large numbers of repeating spike patterns were detected in the original data, equal numbers were detected in the surrogate trains, suggesting that these patterns are chance events. Learning of action through adaptive combination of motor primitives. Thoroughman KA, Shadmehr R: Nature 2000, 407:742-747. • Significance: Moving an arm to a target is an exceedingly complex task from a bio-mechanical viewpoint. One current theory of how the brain controls such a behavior involves the use of a limited set of simpler movement modules or ‘motor primitives’ which can be combined. This work is the strongest evidence to date, albeit somewhat indirect, that the motor system might use motor primitives during a behavior such as adaptation. Findings: Human subjects were trained to move a robot arm to spatial targets in the presence of a complex viscous force field. Initially the movement trajectories were quite disrupted but over time the subjects learned to compensate for, or adapt to, the altered dynamics and produced straight trajectories. By examining the pattern of errors for other movements in the ‘non-learned’ direction the authors found the results consistent with a model in which the motor system learns by combining ‘motor primitives’ that map the desired velocity of the hand to the force required to move the hand at that velocity.
Neurobiology of behaviour Selected by Stephen Goodwin* and Bambos Kyriacou† *University of Glasgow, Glasgow, UK †University of Leicester, Leicester, UK
Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nader K, Schafe GE, Le Doux JE: Nature 2000, 406:722-726. •• Significance: Long-term memories are believed to be consolidated by the remodelling of activated synapses some hours after the expression of the relevant ‘learning genes’. During this
sensitive period, drugs that inhibit protein synthesis can disrupt memory formation. The retrieval of previously consolidated fearassociated memories in rats is also observed to be sensitive to protein inhibitors, suggesting that retrieval of such labile memories requires further protein synthesis for reconsolidation. Findings: The authors used a classical fear-conditioning paradigm in which they coupled an auditory tone (conditioned stimulus) with a mild foot shock (unconditioned stimulus). Regions of the brain implicated in fear conditioning (the lateral and basal nucleii of the amygdala), were injected with an antibiotic 24 h after the initial pairing of CS and US. No effect on the ‘freezing’ fear response measured 24 h after injection was observed (48 h after the initial CS–US pairing). However, if after 24 h from the initial training the CS is presented again followed by an immediate injection (just after the memory is retrieved), 24 h later still the animal’s level of response to the CS is attenuated, as though the initial learning had not been consolidated. This suggests that the initial memory was labile and that retrieving it, even 24 h after memory formation, made it sensitive to decay by the drug-induced inhibition of protein synthesis. These elegant experiments imply that memory consolidation goes through further rounds of reconsolidation before it is set in stone (if it ever is). Increased baseline occupancy of D 2 receptors by dopamine in schizophrenia. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles KS, Weiss R, Cooper TB, Mann J, van Heertum RL et al.: Proc Natl Acad Sci USA 2000, 97:8104-8109. • Significance: The dopamine theory of schizophrenia, in which overstimulation of dopamine receptors is central to the development of the disease, is given a boost by these findings in which brain imaging in schizophrenics and nonschizophrenics is compared. The results reveal that schizophrenic patients have significantly more dopamine D2 receptors, consistent with an increase in dopaminergic activity. Findings: Brain imaging of a control group, in comparison with schizophrenics (matched for age, gender, parental socio-economic status, weight and smoking), revealed no significant differences in striatal D2 availability after administration of a radiolabelled D2 receptor anatagonist. However, after dopamine depletion by prior ingestion of α-methyl-para-tyrosine (α-MPT), schizophrenics showed significantly higher levels of the radiolabelled D2 receptor antagonist, reflecting a greater number of D2 receptors. Comparison of patients that had already previously received chronic D2 receptor antagonist medication with those that had not did not suggest that the enhanced availability of D2 sites in schizophrenics was attributable to previous exposure to these drugs. A relationship between behavior, neurotrophin expression and new neuron survival. Li X-C, Jarvis ED, Alvarez-Borda B, Lim DA, Nottebohn F: Proc Natl Acad Sci USA 2000, 97:8584-8589. • Significance: Changes in the singing behaviour of male canaries are mediated by the act of singing, which enhances the expression of brain-derived neurotrophic factor (BDNF) in the high vocal centre (HVC), which in turn promotes neuronal survival of new HVC neurones. Thus the motor act itself plays a causal role in the remodelling of new pathways during adulthood. Findings: A group of adult male canaries were stimulated to sing by exposure to song playback, and were then divided into two groups, singers and non-singers. Singing birds showed
three times the level of BDNF mRNA compared with nonsingers in the HVC, and 30% more BDNF protein. This enhanced expression of BDNF was limited primarily to the neurons of the HVC that connect to the robust nucleus of the archistriatum (RA) of the descending vocal pathway. In addition, the number of surviving new neurons in the HVC, but not in other brain areas, was significantly increased in the singing group. As BDNF plays a number of roles related to dendritic morphology and synaptogenesis, and BDNF gene expression is regulated by neural activities, it may provide the link between behaviour and plasticity of the nervous system. Whistle matching in wild bottlenose dolphins (Tursiops truncates). Janik VM: Science 2000, 289:1355-1357. • Significance: This report reveals that in their natural conditions, bottlenose dolphins communicate with other individuals by mimicking their whistles, revealing a vocal matching that provides an important step in the evolution of language. Findings: Analysis of spatial relationships between bottlenose dolphins and the type of whistling sounds they emit revealed that individuals mimic sounds and use them to contact other individuals. This vocal matching can occur at distances of up to half a kilometre, and provides a personalised addressing system between two or more individuals. These vocal interactions may be aggressive or may enhance the cohesion of the group and can further aid in discriminating the identity of individuals within the group. A putative pheromone receptor gene expressed in human olfactory mucosa. Rodriguez I, Greer CA, Mok MY, Mombaert P: Nat Genet 2000, 26:18-19. • Significance: Rodriguez et al. report the identification of a putative human pheromone receptor gene. As pheromones are particularly important in mammals for intraspecific communication, particularly between the sexes, this provides a potentially important step for dissecting the olfactory basis for human social cohesion. Findings: Pheromones are airborne molecules produced by an animal that are released into the environment and in turn influence specific physiological or behavioural responses in other members of the corresponding species. In mammals, it has been proposed that these molecules are recognised within the nasal cavity by sensory neurons that express pheromone receptors. Pheromone detection in nonprimate mammals is thought to be accomplished by the vomeronasal organ (VNO), a chemoreceptor organ enclosed in a cartilaginous capsule and separated from the main olfactory epithelium. The vomeronasal neurons have two distinct types of receptor (V1 and V2) that differ from each other and from the large family of odourant receptors. The V1 and V2 genes encode seven-transmembrane proteins. Although it is believed that humans are unlikely to have a functional VNO, it is possible that humans might detect pheromones via the main olfactory organ in a way similar to pigs and rabbits. Rodriguez et al. used both rodent V1r probes and human V1R gene products, obtained by degenerate PCR, for low-stringency hybridisation screening of a human genomic library. The authors identified eight distinct human clones with homology to V1r, but sequence analysis revealed that seven of these are most probably non-functional ‘pseudo-genes’. Sequencing and expression analysis of the last clone has revealed a putative human pheromone receptor gene, which the authors named V1RL1 (V1r-like gene 1).
mab-3 is a direct tra-1 target gene regulating diverse aspects of C. elegans male sexual development and behavior. Yi W, Ross JM, Zarkower D: Development 2000, 127:4469-4480. • Significance: Yi et al. show that the male abnormal gene (mab-3) is under the direct control of the sex determination pathway in specific tissues in C. elegans. This provides a molecular connection between the global regulatory pathway of sexual development and terminal sexual differentiation. Findings: In C. elegans, the tra-1 gene encodes a zinc finger transcription factor, TRA-1A, which regulates, directly or indirectly, all genes required for sexual development. Isolation of targets and partners of TRA-1A will uncover how they affect sexually dimorphic behaviours, and consequently the underlying neural mechanisms involved in these complex behaviours. One example of a downstream sexual regulator in C. elegans is the gene mab-3. In mab-3 mutants, the male intestine produces yolk and cell-proliferation defects occur in the male-specific neurons innervating the ‘sensory rays’ (peripheral sense organs of the male copulatory organ). The mab-3 gene encodes a protein with a related motif to the Drosophila sexual regulatory gene doublesex (dsx). This is intriguing as both genes are known to control, amongst other things, yolk protein gene transcription and sexspecific neuroblast differentiation. Previous work by the authors has shown that Mab-3, in a similar way to DSX proteins, directly regulates transcription of at least one yolk protein gene. Interestingly, this structural and functional similarity observed between phyla suggests a potential universal evolutionary ancestry of at least some aspects of sexual differentiation. Yi et al. have extended their previous study to show that mab-3 is also necessary for the expression of male-specific genes in sensory neurons of the head and tail and for male interaction with hermaphrodites. These roles in male development and behaviour suggest additional functional similarity to dsx.
Neurobiology of disease Selected by Gerd Kempermann* and Juergen Winkler† *Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany †Department of Neurology, University of Regensburg, Germany
β peptide decreases cereNasal administration of amyloid-β bral amyloid burden in a mouse model of Alzheimer’s disease. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe DJ: Ann Neurol 2000, 48:567-579. •• Significance: Progressive cerebral deposition of amyloid-β peptide is an early and essential feature of Alzheimer’s disease (AD), the most common chronic neurodegenerative disorder leading to progressive impairment of memory and cognitive function. Using a novel mucosal immunological approach by which administration of disease-related proteins induced antigen-specific immune responses, the authors were able to demonstrate that Aβ burden and Aβ42 level were decreased in the brains of mice mimicking AD pathology. This immunological approach may be used for the treatment and prevention of AD. Findings: Genetically modified mice overexpressing human amyloid precursor protein 770 (APP770) containing the V717F familial AD mutation under the regulatory control of the plateletderived growth factor-β promotor (which increases the generation of the 42-residue from Aβ) were treated between the ages of 5 and 12 months with human Aβ synthetic peptide mucosally each week. Lower Aβ burden and Aβ levels were accompanied by decreased microglial and astrocytic activation as well as decreased neuritic dystrophy.
Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin NDT, Walsh CA: Nat Genet 2000, 26:93-96. • Significance: In search of genes linked to severe developmental disorders in which neuronal migration is impaired, the authors link an autosomal recessive form of lissencephaly (LCH) to two independent mutations in the human gene encoding reelin (RELN) on chromosome 7q22. This study links the reeler mouse mutant with this human disorder in order to elucidate the role of reelin inside and outside the brain. Findings: Reelin is encoded by 65 exons, covering more than 400 kb of genomic DNA and 12 kb of coding cDNA. Affected LCH patients with a Saudi Arabian pedigree showed a mutation at the splice acceptor region on exon 36, and patients with a British pedigree the removal of exon 42 producing a translational frameshift and early termination. In addition to severe malformations of the cerebellum, hippocampus and brainstem, some patients with the RELN mutation show abnormal neuromuscular connectivity and lymphoedema, suggesting that reelin also has functions outside the brain. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandbrock AW, and the CHAMPS Group: N Engl J Med 2000, 343:898-904. •• Significance: Interferon-β has demonstrable benefits in the treatment of patients with established MS, including the reduction of clinical relapses and brain lesions. This study demonstrates for the first time that initiating treatment with interferon β-1a at the time of the first demyelinating event is beneficial for those patients with prior subclinical demyelinating lesions when assessed using magnetic resonance imaging (MRI). This early treatment may help to prevent a second attack of MS and may reduce the progression of the disease. Findings: This is the first prospective, randomized, double-blind study of 383 patients testing the efficacy of interferon β-1a in patients who had both experienced a first acute demyelinating event and had MRI evidence of prior demyelinating attacks. After initial corticosteroid treatment, patients were randomly treated with weekly, intramuscular injections of interferon β-1a or placebo. The trial was stopped because a preplanned interim efficacy analysis revealed a highly significant improvement in the interferon β-1a group. The size and number of brain lesions were significantly lower in the group treated with interferon beta-1a. Potent analgesic effects of GDNF in neuropathic pain states. Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN, McMahon SB: Science 2000, 290:124-127. • Significance: In the past, growth factors and neurotrophic factors have been heralded as powerful and promising agents for neurological therapy, but the great expectations have generally not been met whenever therapies based on neurotrophic factors have (often prematurely) been brought to the clinics. In contrast, in this study, Boucher et al. present an animal model to mimic chronic damage of the peripheral nervous system and the therapeutic use of glialcell-line-derived neurotrophic factor (GDNF) to treat neuropathic pain. GDNF is found to ameliorate neuropathic pain when several outcome measures are tested, including electrophysiology. Findings: In rat models of partial ligation of the sciatic nerve or spinal nerve ligation, intrathecally applied GDNF resulted in a prevention and a reversal of mechanical and thermal hyperalgesia,
whereas nerve growth factor (NGF) and neurturin 3 (NT3) had no effect on the emergence of these conditions. There also was no effect of GDNF on pain-related behavior in normal animals. A transgenic mouse model for inducible and reversible dysmyelination. Mathis C, Hindelang C, LeMeur M, Borrelli E: J Neurosci 2000, 20:7698-7705. • Significance: This study introduces an interesting new mouse model for inducible dysmyelination in vivo. The key significance lies in the fact that the damage is inducible in a dose- and timedependent manner and allows investigations at different postnatal developmental stages. Findings: In the transgenic model used here, ablation of oligodendrocytes is induced by a synergistic effect of the transgene herpes virus 1 thymidine kinase under the control of the myelin basic protein promoter and the independent systemic injection of a nucleoside analog. When the toxin is present only in the first days of the vulnerable postnatal myelination period, no strong phenotype develops, suggesting that continued myelinogenesis can compensate for the loss of oligodendrocytes. Beyond this developmental stage, however, no true reversibility is seen. Reduced number of hypocretin neurons in human narcolepsy. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM: Neuron 2000, 27:469-474. AND
A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charney Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R et al.: Nat Neurosci 2000, 6:991-997.
• Significance: These two reports provide the first evidence that a malfunction in the hypocretin system might underlie narcolepsy in humans. Findings: The hypocretins are neurotransmitters produced by a very small number of neurons in the lateral hypothalamus and the perifornical area, the axons of which project to almost the entire brain. Thannickal et al. examined post-mortem tissue from four narcoleptics and twelve healthy individuals and found a reduction of hypocretin neurons by 85–95% in the narcoleptics. Peyron et al. performed in situ hybridization and peptide radioimmunoassays to describe a general loss of hypocretins in the brains of six narcoleptics. A hypothesis regarding the way in which this presumed loss of function leads to the complex picture of symptoms in narcolepsy remains to be established.
Corrigendum Stephen Goodwin* and Bambos Kyriacou† *University of Glasgow, Glasgow, UK †University of Leicester, Leicester, UK
On page 430 of the August 2000 issue we published a Paper alert feature on the paper “Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype” by McKernan et al. (Nat Neurosci 2000, 3:587-592). We incorrectly stated that McKernan et al. showed that benzodiazepine-induced anxiolysis was normal in transgenic α1 (H101R) mice. In fact, Rudolph et al. (Nature 1999, 401:796-800) had previously shown that transgenic α1 (H101R) mice show normal BDZ-induced anxiolysis. McKernan et al. had actually used rats to assess anxiolysis by exploiting a selective BDZ-site ligand. We apologise for our factual errors and wish to reiterate that findings from both groups revealed that the α1 subtype mediates the sedative, but not the anxiolytic effects of BDZs.