Hot off the presses! Dec 24 Neuron

The Dec 24 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• α-Synuclein and LRRK2: Partners in Crime
  - Neuron 64(6):771-773 (2009)
  In this issue of Neuron, Lin et al. report that LRRK2 modulates age-related neurodegeneration caused by overexpression of α-synuclein in the forebrain of transgenic mice. Overexpression of LRRK2 accelerates the progression of α-synuclein-mediated neuropathological changes, whereas deletion of LRRK2 alleviates these alterations. The results reveal an interesting interaction between α-synuclein and LRRK2, two gene products linked to dominantly inherited Parkinson's disease.
• RETouching upon Mechanoreceptors
  - Neuron 64(6):773-776 (2009)
  The rapidly adapting (RA) low-threshold mechanoreceptors respond to movement of the skin and vibration and are critical for the perception of texture and shape. In this issue of Neuron, two papers (Bourane et al. and Luo et al.) demonstrate that early-born Ret+ sensory neurons are RA mechanoreceptors, whose peripheral nerve terminals are associated with Meissner corpuscles, longitudinal lanceolate endings, and Pacinian corpuscles. The studies further show that Ret signaling is essential for the development of these mechanoreceptors.
• A Molecular Sensor for the Baroreceptor Reflex?
  - Neuron 64(6):776-777 (2009)
  The reflex that provides rapid neural control of blood pressure is triggered by an unknown molecular pressure sensor. ASIC2, an ion channel in a family that includes a mechanosensor from C. elegans, is shown by Lu et al. in this issue of Neuron to be critical for this reflex in mice, perhaps because ASIC2 is the elusive pressure sensor.
• The V1 Population Gains Normalization
  - Neuron 64(6):778-780 (2009)
  In this issue of Neuron, Busse et al. describe the population response to superimposed visual stimuli while Sit et al. examine the spatiotemporal evolution of cortical activation in response to small visual stimuli. Surprisingly, these two studies of V1 report that a single gain control model accounts for their results.
• Discreet Charm of the GABAergic Bourgeoisie: Superconnected Cells Conduct Developmental Symphonies
  - Neuron 64(6):780-782 (2009)
  In an exciting study in the December 4th issue of Science, Bonifazi and colleagues demonstrated the existence and importance of exceedingly rare but unusually richly connected cells in the developing hippocampus. Manipulating the activity of single GABAergic hub cells modulated network activity patterns, demonstrating their importance for coordinating synchronous activity.
• The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids
  - Neuron 64(6):783-790 (2009)
  Recent reports indicate that a growing number of intracellular proteins are not only prone to pathological aggregation but can also be released and "infect" neighboring cells. Therefore, many complex diseases may obey a simple model of propagation where the penetration of seeds into hosts determines spatial spread and disease progression. We term these proteins prionoids, as they appear to infect their neighbors just like prions—but how can bulky protein aggregates be released from cells and how do they access other cells? The widespread existence of such prionoids raises unexpected issues that question our understanding of basic cell biology.
• LRRTM2 Functions as a Neurexin Ligand in Promoting Excitatory Synapse Formation
  - Neuron 64(6):791-798 (2009)
  Recently, leucine-rich repeat transmembrane proteins (LRRTMs) were found to be synaptic cell-adhesion molecules that, when expressed in nonneuronal cells, induce presynaptic differentiation in contacting axons. We now demonstrate that LRRTM2 induces only excitatory synapses, and that it also acts to induce synapses in transfected neurons similarly to neuroligin-1. Using affinity chromatography, we identified α- and β-neurexins as LRRTM2 ligands, again rendering LRRTM2 similar to neuroligin-1. However, whereas neuroligins bind neurexins containing or lacking an insert in splice site #4, LRRTM2 only binds neurexins lacking an insert in splice site #4. Binding of neurexins to LRRTM2 can produce cell-adhesion junctions, consistent with a trans-interaction regulated by neurexin alternative splicing, and recombinant neurexin-1β blocks LRRTM2's ability to promote presynaptic differentiation. Thus, our data suggest that two unrelated postsynaptic cell-adhesion molecules, ! LRRTMs and neuroligins, unexpectedly bind to neurexins as the same presynaptic receptor, but that their binding is subject to distinct regulatory mechanisms.
• LRRTM2 Interacts with Neurexin1 and Regulates Excitatory Synapse Formation
  - Neuron 64(6):799-806 (2009)
  We identify the leucine-rich repeat transmembrane protein LRRTM2 as a key regulator of excitatory synapse development and function. LRRTM2 localizes to excitatory synapses in transfected hippocampal neurons, and shRNA-mediated knockdown of LRRTM2 leads to a decrease in excitatory synapses without affecting inhibitory synapses. LRRTM2 interacts with PSD-95 and regulates surface expression of AMPA receptors, and lentivirus-mediated knockdown of LRRTM2 in vivo decreases the strength of evoked excitatory synaptic currents. Structure-function studies indicate that LRRTM2 induces presynaptic differentiation via the extracellular LRR domain. We identify Neurexin1 as a receptor for LRRTM2 based on affinity chromatography. LRRTM2 binds to both Neurexin 1α and Neurexin 1β, and shRNA-mediated knockdown of Neurexin1 abrogates LRRTM2-induced presynaptic differentiation. These observations indicate that an LRRTM2-Neurexin1 interaction plays a critical role in regulating excitatory! synapse development.
• Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's-Disease-Related Mutant α-synuclein
  - Neuron 64(6):807-827 (2009)
  Mutations in α-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T α-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of α-synuclein in A53T mice, which likely resulted from the impairment of microtubule dynamics, Golgi organization, and the ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of α-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings de! monstrate that overexpression of LRRK2 enhances α-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating α-synuclein-induced neurodegeneration.
• Serines 13 and 16 Are Critical Determinants of Full-Length Human Mutant Huntingtin Induced Disease Pathogenesis in HD Mice
  - Neuron 64(6):828-840 (2009)
  The N-terminal 17 amino acids of huntingtin (NT17) can be phosphorylated on serines 13 and 16; however, the significance of these modifications in Huntington's disease pathogenesis remains unknown. In this study, we developed BAC transgenic mice expressing full-length mutant huntingtin (fl-mhtt) with serines 13 and 16 mutated to either aspartate (phosphomimetic or SD) or alanine (phosphoresistant or SA). Both mutant proteins preserve the essential function of huntingtin in rescuing knockout mouse phenotypes. However, fl-mhtt-induced disease pathogenesis, including motor and psychiatric-like behavioral deficits, mhtt aggregation, and selective neurodegeneration are abolished in SD but preserved in SA mice. Moreover, modification of these serines in expanded repeat huntingtin peptides modulates aggregation and amyloid fibril formation in vitro. Together, our findings demonstrate that serines 13 and 16 are critical determinants of fl-mhtt-induced disease pathogenesis in v! ivo, supporting the targeting of huntingtin NT17 domain and its modifications in HD therapy.
• Molecular Identification of Rapidly Adapting Mechanoreceptors and Their Developmental Dependence on Ret Signaling
  - Neuron 64(6):841-856 (2009)
  In mammals, the first step in the perception of form and texture is the activation of trigeminal or dorsal root ganglion (DRG) mechanosensory neurons, which are classified as either rapidly (RA) or slowly adapting (SA) according to their rates of adaptation to sustained stimuli. The molecular identities and mechanisms of development of RA and SA mechanoreceptors are largely unknown. We found that the "early Ret+" DRG neurons are RA mechanoreceptors, which form Meissner corpuscles, Pacinian corpuscles, and longitudinal lanceolate endings. The central projections of these RA mechanoreceptors innervate layers III through V of the spinal cord and terminate within discrete subdomains of the dorsal column nuclei. Moreover, mice lacking Ret signaling components are devoid of Pacinian corpuscles and exhibit a dramatic disruption of RA mechanoreceptor projections to both the spinal cord and medulla. Thus, the early Ret+ neurons are RA mechanoreceptors and Ret signaling is r! equired for the assembly of neural circuits underlying touch perception.
• Low-Threshold Mechanoreceptor Subtypes Selectively Express MafA and Are Specified by Ret Signaling
  - Neuron 64(6):857-870 (2009)
  Low-threshold mechanoreceptor neurons (LTMs) of the dorsal root ganglia (DRG) are essential for touch sensation. They form highly specialized terminations in the skin and display stereotyped projections in the spinal cord. Functionally defined LTMs depend on neurotrophin signaling for their postnatal survival and functioning, but how these neurons arise during development is unknown. Here, we show that specific types of LTMs can be identified shortly after DRG genesis by unique expression of the MafA transcription factor, the Ret receptor and coreceptor GFRα2, and find that their specification is Ngn2 dependent. In mice lacking Ret, these LTMs display early differentiation defects, as revealed by reduced MafA expression, and at later stages their central and peripheral projections are compromised. Moreover, in MafA mutants, a discrete subset of LTMs display altered expression of neurotrophic factor receptors. Our results provide evidence that genetic interactions invo! lving Ret and MafA progressively promote the differentiation and diversification of LTMs.
• A Coordinated Local Translational Control Point at the Synapse Involving Relief from Silencing and MOV10 Degradation
  - Neuron 64(6):871-884 (2009)
  Persistent changes in synaptic strength are locally regulated by both protein degradation and synthesis; however, the coordination of these opposing limbs is poorly understood. Here, we found that the RISC protein MOV10 was present at synapses and was rapidly degraded by the proteasome in an NMDA-receptor-mediated activity-dependent manner. We designed a translational trap to capture those mRNAs whose spatiotemporal translation is regulated by MOV10. When MOV10 was suppressed, a set of mRNAs—including α-CaMKII, Limk1, and the depalmitoylating enzyme lysophospholipase1 (Lypla1)—selectively entered the polysome compartment. We also observed that Lypla1 mRNA is associated with the brain-enriched microRNA miR-138. Using a photoconvertible translation reporter, Kaede, we analyzed the activity-dependent protein synthesis driven by Lypla1 and α-CaMKII 3′UTRs. We established this protein synthesis to be MOV10 and proteasome dependent. These results suggest a unifying p! icture of a local translational regulatory mechanism during synaptic plasticity.
• The Ion Channel ASIC2 Is Required for Baroreceptor and Autonomic Control of the Circulation
  - Neuron 64(6):885-897 (2009)
  Arterial baroreceptors provide a neural sensory input that reflexly regulates the autonomic drive of circulation. Our goal was to test the hypothesis that a member of the acid-sensing ion channel (ASIC) subfamily of the DEG/ENaC superfamily is an important determinant of the arterial baroreceptor reflex. We found that aortic baroreceptor neurons in the nodose ganglia and their terminals express ASIC2. Conscious ASIC2 null mice developed hypertension, had exaggerated sympathetic and depressed parasympathetic control of the circulation, and a decreased gain of the baroreflex, all indicative of an impaired baroreceptor reflex. Multiple measures of baroreceptor activity each suggest that mechanosensitivity is diminished in ASIC2 null mice. The results define ASIC2 as an important determinant of autonomic circulatory control and of baroreceptor sensitivity. The genetic disruption of ASIC2 recapitulates the pathological dysautonomia seen in heart failure and hypertension and! defines a molecular defect that may be relevant to its development.
• Sodium Entry during Action Potentials of Mammalian Neurons: Incomplete Inactivation and Reduced Metabolic Efficiency in Fast-Spiking Neurons
  - Neuron 64(6):898-909 (2009)
  We measured the time course of sodium entry during action potentials of mouse central neurons at 37°C to examine how efficiently sodium entry is coupled to depolarization. In cortical pyramidal neurons, sodium entry was nearly completely confined to the rising phase of the spike: only 25% more sodium enters than the theoretical minimum necessary for spike depolarization. However, in fast-spiking GABAergic neurons (cerebellar Purkinje cells and cortical interneurons), twice as much sodium enters as the theoretical minimum. The extra entry occurs because sodium channel inactivation is incomplete during the falling phase of the spike. The efficiency of sodium entry in different cell types is primarily a function of action potential shape and not cell-type-specific differences in sodium channel kinetics. The narrow spikes of fast-spiking GABAergic neurons result in incomplete inactivation of sodium channels; this reduces metabolic efficiency but likely enhances the abilit! y to fire spikes at high frequency.
• Rewarded Outcomes Enhance Reactivation of Experience in the Hippocampus
  - Neuron 64(6):910-921 (2009)
  Remembering experiences that lead to reward is essential for survival. The hippocampus is required for forming and storing memories of events and places, but the mechanisms that associate specific experiences with rewarding outcomes are not understood. Event memory storage is thought to depend on the reactivation of previous experiences during hippocampal sharp wave ripples (SWRs). We used a sequence switching task that allowed us to examine the interaction between SWRs and reward. We compared SWR activity after animals traversed spatial trajectories and either received or did not receive a reward. Here, we show that rat hippocampal CA3 principal cells are significantly more active during SWRs following receipt of reward. This SWR activity was further enhanced during learning and reactivated coherent elements of the paths associated with the reward location. This enhanced reactivation in response to reward could be a mechanism to bind rewarding outcomes to the experien! ces that precede them.
• Corticospinal Neurons in Macaque Ventral Premotor Cortex with Mirror Properties: A Potential Mechanism for Action Suppression?
  - Neuron 64(6):922-930 (2009)
  The discovery of "mirror neurons" in area F5 of the ventral premotor cortex has prompted many theories as to their possible function. However, the identity of mirror neurons remains unknown. Here, we investigated whether identified pyramidal tract neurons (PTNs) in area F5 of two adult macaques exhibited "mirror-like" activity. About half of the 64 PTNs tested showed significant modulation of their activity while monkeys observed precision grip of an object carried out by an experimenter, with somewhat fewer showing modulation during precision grip without an object or grasping concealed from the monkey. Therefore, mirror-like activity can be transmitted directly to the spinal cord via PTNs. A novel finding is that many PTNs (17/64) showed complete suppression of discharge during action observation, while firing actively when the monkey grasped food rewards. We speculate that this suppression of PTN discharge might be involved in the inhibition of self-movement! during action observation.
• Representation of Concurrent Stimuli by Population Activity in Visual Cortex
  - Neuron 64(6):931-942 (2009)
  How do neuronal populations represent concurrent stimuli? We measured population responses in cat primary visual cortex (V1) using electrode arrays. Population responses to two superimposed gratings were weighted sums of the individual grating responses. The weights depended strongly on the relative contrasts of the gratings. When the contrasts were similar, the population performed an approximately equal summation. When the contrasts differed markedly, however, the population performed approximately a winner-take-all competition. Stimuli that were intermediate to these extremes elicited intermediate responses. This entire range of behaviors was explained by a single model of contrast normalization. Normalization captured both the spike responses and the local field potential responses; it even predicted visually evoked currents source-localized to V1 in human subjects. Normalization has profound effects on V1 population responses and is likely to shape the interpretat! ion of these responses by higher cortical areas.
• Complex Dynamics of V1 Population Responses Explained by a Simple Gain-Control Model
  - Neuron 64(6):943-956 (2009)
  To understand sensory encoding and decoding, it is essential to characterize the dynamics of population responses in sensory cortical areas. Using voltage-sensitive dye imaging in awake, fixating monkeys, we obtained complete quantitative measurements of the spatiotemporal dynamics of V1 responses over the entire region activated by small, briefly presented stimuli. The responses exhibit several complex properties: they begin to rise approximately simultaneously over the entire active region, but reach their peak more rapidly at the center. However, at stimulus offset the responses fall simultaneously and at the same rate at all locations. Although response onset depends on stimulus contrast, both the peak spatial profile and the offset dynamics are independent of contrast. We show that these results are consistent with a simple population gain-control model that generalizes earlier single-neuron contrast gain-control models. This model provides valuable insight and is! likely to be applicable to other brain areas.
• Reviewer List for 2009
  - Neuron 64(6):I-VIII (2009)