Hot off the presses! Sep 22 Neuron

The Sep 22 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:

• Wnt Signaling as a Potential Therapeutic Target for Frontotemporal Dementia
  - Neuron 71(6):955-957 (2011)
  Progranulin mutations result in frontotemporal dementia, but the underlying pathophysiology has remained largely unexplained. New data by Geschwind and colleagues in this issue of Neuron uncovered that the Wnt/FZD2 signaling pathway is an early and critical contributor to disease pathology.
• Patterning Spinal Motor Activity in the Absence of Synaptic Excitation
  - Neuron 71(6):957-959 (2011)
  Alternate activation of antagonistic muscles across a joint is essential for movement. A new study, by Talpalar et al., in this issue of Neuron highlights the importance of spinal cord inhibitory interneurons in generating motor activity by showing that they can generate alternating flexor-extensor motor neuron firing in the absence of glutamatergic synaptic input.
• The Dynamics of Learning and Behavioral Flexibility
  - Neuron 71(6):959-961 (2011)
  Fundamental to behavior is the capacity to distinguish beneficial from detrimental environmental stimuli. In this issue of Neuron, a new study by Morrison et al. shows that underlying these processes are qualitatively different dynamical interactions between brain structures involved in processing the value of environmental stimuli.
• All in a Sniff: Olfaction as a Model for Active Sensing
  - Neuron 71(6):962-973 (2011)
  Sensation is an active process involving the sampling and central processing of external stimuli selectively in space and time. Olfaction in particular depends strongly on active sensing due to the fact that—at least in mammals—inhalation of air into the nasal cavity is required for odor detection. This seemingly simple first step in odor sensation profoundly shapes nearly all aspects of olfactory system function, from the distribution of odorant receptors to the functional organization of central processing to the perception of odors. The dependence of olfaction on inhalation also allows for profound modulation of olfactory processing by changes in odor sampling strategies in coordination with attentional state and sensory demands. This review discusses the role of active sensing in shaping olfactory system function at multiple levels and draws parallels with other sensory modalities to highlight the importance of an active sensing perspective in understanding how! sensory systems work in the behaving animal.
• Seeing Things in Motion: Models, Circuits, and Mechanisms
  - Neuron 71(6):974-994 (2011)
  Motion vision provides essential cues for navigation and course control as well as for mate, prey, or predator detection. Consequently, neurons responding to visual motion in a direction-selective way are found in almost all species that see. However, directional information is not explicitly encoded at the level of a single photoreceptor. Rather, it has to be computed from the spatio-temporal excitation level of at least two photoreceptors. How this computation is done and how this computation is implemented in terms of neural circuitry and membrane biophysics have remained the focus of intense research over many decades. Here, we review recent progress made in this area with an emphasis on insects and the vertebrate retina.
• A Resource of Cre Driver Lines for Genetic Targeting of GABAergic Neurons in Cerebral Cortex
  - Neuron 71(6):995-1013 (2011)
  A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and beha! vior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain.
• Development of Cell Type-Specific Connectivity Patterns of Converging Excitatory Axons in the Retina
  - Neuron 71(6):1014-1021 (2011)
  To integrate information from different presynaptic cell types, dendrites receive distinct patterns of synapses from converging axons. How different afferents in vivo establish specific connectivity patterns with the same dendrite is poorly understood. Here, we examine the synaptic development of three glutamatergic bipolar cell types converging onto a common postsynaptic retinal ganglion cell. We find that after axons and dendrites target appropriate synaptic layers, patterns of connections among these neurons diverge through selective changes in the conversion of axo-dendritic appositions to synapses. This process is differentially regulated by neurotransmission, which is required for the shift from single to multisynaptic appositions of one bipolar cell type but not for maintenance and elimination, respectively, of connections from the other two types. Thus, synaptic specificity among converging excitatory inputs in the retina emerges via differential synaptic matur! ation of axo-dendritic appositions and is shaped by neurotransmission in a cell type-dependent manner.
• Regulation of AMPA Receptor Function by the Human Memory-Associated Gene KIBRA
  - Neuron 71(6):1022-1029 (2011)
  KIBRA has recently been identified as a gene associated with human memory performance. Despite the elucidation of the role of KIBRA in several diverse processes in nonneuronal cells, the molecular function of KIBRA in neurons is unknown. We found that KIBRA directly binds to the protein interacting with C-kinase 1 (PICK1) and forms a complex with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs), the major excitatory neurotransmitter receptors in the brain. KIBRA knockdown accelerates the rate of AMPAR recycling following N-methyl-D-aspartate receptor-induced internalization. Genetic deletion of KIBRA in mice impairs both long-term depression and long-term potentiation at hippocampal Schaffer collateral-CA1 synapses. Moreover, KIBRA knockout mice have severe deficits in contextual fear learning and memory. These results indicate that KIBRA regulates higher brain function by regulating AMPAR trafficking and synaptic plasticity.
• Functional Genomic Analyses Identify Pathways Dysregulated by Progranulin Deficiency, Implicating Wnt Signaling
  - Neuron 71(6):1030-1042 (2011)
  Progranulin (GRN) mutations cause frontotemporal dementia (FTD), but GRN's function in the CNS remains largely unknown. To identify the pathways downstream of GRN, we used weighted gene coexpression network analysis (WGCNA) to develop a systems-level view of transcriptional alterations in a human neural progenitor model of GRN-deficiency. This highlighted key pathways such as apoptosis and ubiquitination in GRN deficient human neurons, while revealing an unexpected major role for the Wnt signaling pathway, which was confirmed by analysis of gene expression data from postmortem FTD brain. Furthermore, we observed that the Wnt receptor Fzd2 was one of only a few genes upregulated at 6 weeks in a GRN knockout mouse, and that FZD2 reduction caused increased apoptosis, while its upregulation promoted neuronal survival in vitro. Together, these in vitro and in vivo data point to an adaptive role for altered Wnt signaling in GRN deficiency-mediated FTD, representing a potenti! al therapeutic target. Video Abstract View Within Article
• Axon Regeneration Pathways Identified by Systematic Genetic Screening in C. elegans
  - Neuron 71(6):1043-1057 (2011)
  The mechanisms underlying the ability of axons to regrow after injury remain poorly explored at the molecular genetic level. We used a laser injury model in Caenorhabditis elegans mechanosensory neurons to screen 654 conserved genes for regulators of axonal regrowth. We uncover several functional clusters of genes that promote or repress regrowth, including genes classically known to affect axon guidance, membrane excitability, neurotransmission, and synaptic vesicle endocytosis. The conserved Arf Guanine nucleotide Exchange Factor (GEF), EFA-6, acts as an intrinsic inhibitor of regrowth. By combining genetics and in vivo imaging, we show that EFA-6 inhibits regrowth via microtubule dynamics, independent of its Arf GEF activity. Among newly identified regrowth inhibitors, only loss of function in EFA-6 partially bypasses the requirement for DLK-1 kinase. Identification of these pathways significantly expands our understanding of the genetic basis of axonal injury respo! nses and repair.
• GDE2 Regulates Subtype-Specific Motor Neuron Generation through Inhibition of Notch Signaling
  - Neuron 71(6):1058-1070 (2011)
  The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates! within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons.
• Identification of Minimal Neuronal Networks Involved in Flexor-Extensor Alternation in the Mammalian Spinal Cord
  - Neuron 71(6):1071-1084 (2011)
  Neural networks in the spinal cord control two basic features of locomotor movements: rhythm generation and pattern generation. Rhythm generation is generally considered to be dependent on glutamatergic excitatory neurons. Pattern generation involves neural circuits controlling left-right alternation, which has been described in great detail, and flexor-extensor alternation, which remains poorly understood. Here, we use a mouse model in which glutamatergic neurotransmission has been ablated in the locomotor region of the spinal cord. The isolated in vitro spinal cord from these mice produces locomotor-like activity—when stimulated with neuroactive substances—with prominent flexor-extensor alternation. Under these conditions, unlike in control mice, networks of inhibitory interneurons generate the rhythmic activity. In the absence of glutamatergic synaptic transmission, the flexor-extensor alternation appears to be generated by Ia inhibitory interneurons, which medi! ate reciprocal inhibition from muscle proprioceptors to antagonist motor neurons. Our study defines a minimal inhibitory network that is needed to produce flexor-extensor alternation during locomotion.
• Distinct Modes of AMPA Receptor Suppression at Developing Synapses by GluN2A and GluN2B: Single-Cell NMDA Receptor Subunit Deletion In Vivo
  - Neuron 71(6):1085-1101 (2011)
  During development there is an activity-dependent switch in synaptic N-Methyl-D-aspartate (NMDA) receptor subunit composition from predominantly GluN2B to GluN2A, though the precise role of this switch remains unknown. By deleting GluN2 subunits in single neurons during synaptogenesis, we find that both GluN2B and GluN2A suppress AMPA receptor expression, albeit by distinct means. Similar to GluN1, GluN2B deletion increases the number of functional synapses, while GluN2A deletion increases the strength of unitary connections without affecting the number of functional synapses. We propose a model of excitatory synapse maturation in which baseline activation of GluN2B-containing receptors prevents premature synapse maturation until correlated activity allows induction of functional synapses. This activity also triggers the switch to GluN2A, which dampens further potentiation. Furthermore, we analyze the subunit composition of synaptic NMDA receptors in CA1 pyramidal cell! s, provide electrophysiological evidence for a large population of synaptic triheteromeric receptors, and estimate the subunit-dependent open probability.
• DPP6 Establishes the A-Type K+ Current Gradient Critical for the Regulation of Dendritic Excitability in CA1 Hippocampal Neurons
  - Neuron 71(6):1102-1115 (2011)
  Subthreshold-activating A-type K+ currents are essential for the proper functioning of the brain, where they act to delay excitation and regulate firing frequency. In CA1 hippocampal pyramidal neuron dendrites, the density of A-type K+ current increases with distance from the soma, playing an important role in synaptic integration and plasticity. The mechanism underlying this gradient has, however, remained elusive. Here, dendritic recordings from mice lacking the Kv4 transmembrane auxiliary subunit DPP6 revealed that this protein is critical for generating the A-current gradient. Loss of DPP6 led to a decrease in A-type current, specifically in distal dendrites. Decreased current density was accompanied by a depolarizing shift in the voltage dependence of channel activation. Together these changes resulted in hyperexcitable dendrites with enhanced dendritic AP back-propagation, calcium electrogenesis, and induction of synaptic long-term potentiation. Despite enhanced ! dendritic excitability, firing behavior evoked by somatic current injection was mainly unaffected in DPP6-KO recordings, indicating compartmentalized regulation of neuronal excitability.
• Vesicular Zinc Promotes Presynaptic and Inhibits Postsynaptic Long-Term Potentiation of Mossy Fiber-CA3 Synapse
  - Neuron 71(6):1116-1126 (2011)
  The presence of zinc in glutamatergic synaptic vesicles of excitatory neurons of mammalian cerebral cortex suggests that zinc might regulate plasticity of synapses formed by these neurons. Long-term potentiation (LTP) is a form of synaptic plasticity that may underlie learning and memory. We tested the hypothesis that zinc within vesicles of mossy fibers (mf) contributes to mf-LTP, a classical form of presynaptic LTP. We synthesized an extracellular zinc chelator with selectivity and kinetic properties suitable for study of the large transient of zinc in the synaptic cleft induced by mf stimulation. We found that vesicular zinc is required for presynaptic mf-LTP. Unexpectedly, vesicular zinc also inhibits a form of postsynaptic mf-LTP. Because the mf-CA3 synapse provides a major source of excitatory input to the hippocampus, regulating its efficacy by these dual actions, vesicular zinc is critical to proper function of hippocampal circuitry in health and disease.
• Different Time Courses for Learning-Related Changes in Amygdala and Orbitofrontal Cortex
  - Neuron 71(6):1127-1140 (2011)
  The orbitofrontal cortex (OFC) and amygdala are thought to participate in reversal learning, a process in which cue-outcome associations are switched. However, current theories disagree on whether OFC directs reversal learning in the amygdala. Here, we show that during reversal of cues' associations with rewarding and aversive outcomes, neurons that respond preferentially to stimuli predicting aversive events update more quickly in amygdala than OFC; meanwhile, OFC neurons that respond preferentially to reward-predicting stimuli update more quickly than those in the amygdala. After learning, however, OFC consistently differentiates between impending reinforcements with a shorter latency than the amygdala. Finally, analysis of local field potentials (LFPs) reveals a disproportionate influence of OFC on amygdala that emerges after learning. We propose that reversal learning is supported by complex interactions between neural circuits spanning the amygdala and OFC, rather! than directed by any single structure.
• Hedging Your Bets by Learning Reward Correlations in the Human Brain
  - Neuron 71(6):1141-1152 (2011)
  Human subjects are proficient at tracking the mean and variance of rewards and updating these via prediction errors. Here, we addressed whether humans can also learn about higher-order relationships between distinct environmental outcomes, a defining ecological feature of contexts where multiple sources of rewards are available. By manipulating the degree to which distinct outcomes are correlated, we show that subjects implemented an explicit model-based strategy to learn the associated outcome correlations and were adept in using that information to dynamically adjust their choices in a task that required a minimization of outcome variance. Importantly, the experimentally generated outcome correlations were explicitly represented neuronally in right midinsula with a learning prediction error signal expressed in rostral anterior cingulate cortex. Thus, our data show that the human brain represents higher-order correlation structures between rewards, a core adaptive abi! lity whose immediate benefit is optimized sampling.