Hot off the presses! Dec 22 Neuron

The Dec 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:

• Rate Remapping: When the Code Goes beyond Space
  - Neuron (Cambridge Mass ) 68(6):1015-1016 (2010)
  Rate remapping is a conjunctive code that potentially enables hippocampal place cells to jointly represent spatial and nonspatial information. In this issue of Neuron, Rennó-Costa et al. introduce a theoretical model wherein the convergence of the medial and lateral entorhinal excitatory inputs, combined with local inhibition, explains hippocampal rate remapping.
• In a Pickle: Is Cornichon Just Relish or Part of the Main Dish?
  - Neuron (Cambridge Mass ) 68(6):1017-1019 (2010)
  The recent discovery that vertebrate homologs of Drosophila cornichon associate with AMPA receptors led to the unexpected notion that cornichons play a role in synaptic transmission. In this issue of Neuron, Kato et al. find that cornichons modulate the gating of TARP-associated AMPA receptors by preventing their resensitization to glutamate.
• Multiple Functions of the Vesicular Proton Pump in Nerve Terminals
  - Neuron (Cambridge Mass ) 68(6):1020-1022 (2010)
  Synaptic vesicles are acidified by a proton pump (vATPase), which allows vesicular uptake of neurotransmitters. After vesicle exocytosis, continued operation of the vATPase would seem to serve no useful function. In this issue of Neuron, however, Zhang and colleagues show that continued pumping alkalinizes the cytoplasm, accelerating endocytosis.
• Sleep State Switching
  - Neuron (Cambridge Mass ) 68(6):1023-1042 (2010)
  We take for granted the ability to fall asleep or to snap out of sleep into wakefulness, but these changes in behavioral state require specific switching mechanisms in the brain that allow well-defined state transitions. In this review, we examine the basic circuitry underlying the regulation of sleep and wakefulness and discuss a theoretical framework wherein the interactions between reciprocal neuronal circuits enable relatively rapid and complete state transitions. We also review how homeostatic, circadian, and allostatic drives help regulate sleep state switching and discuss how breakdown of the switching mechanism may contribute to sleep disorders such as narcolepsy.
• An Embedded Subnetwork of Highly Active Neurons in the Neocortex
  - Neuron (Cambridge Mass ) 68(6):1043-1050 (2010)
  Unbiased methods to assess the firing activity of individual neurons in the neocortex have revealed that a large proportion of cells fire at extremely low rates (<0.1 Hz), both in their spontaneous and evoked activity. Thus, firing in neocortical networks appears to be dominated by a small population of highly active neurons. Here, we use a fosGFP transgenic mouse to examine the properties of cells with a recent history of elevated activity. FosGFP-expressing layer 2/3 pyramidal cells fired at higher rates compared to fosGFP− neurons, both in vivo and in vitro. Elevated activity could be attributed to increased excitatory and decreased inhibitory drive to fosGFP+ neurons. Paired-cell recordings indicated that fosGFP+ neurons had a greater likelihood of being connected to each other. These findings indicate that highly active, interconnected neuronal ensembles are present in the neocortex and suggest these cells may play a role in the encoding of sensory information. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (11811 K)
• The Mechanism of Rate Remapping in the Dentate Gyrus
  - Neuron (Cambridge Mass ) 68(6):1051-1058 (2010)
  Rate remapping is a recently revealed neural code in which sensory information modulates the firing rate of hippocampal place cells. The mechanism underlying rate remapping is unknown. Its characteristic modulation, however, must arise from the interaction of the two major inputs to the hippocampus, the medial entorhinal cortex (MEC), in which grid cells represent the spatial position of the rat, and the lateral entorhinal cortex (LEC), in which cells represent the sensory properties of the environment. We have used computational methods to elucidate the mechanism by which this interaction produces rate remapping. We show that the convergence of LEC and MEC inputs, in conjunction with a competitive network process mediated by feedback inhibition, can account quantitatively for this phenomenon. The same principle accounts for why different place fields of the same cell vary independently as sensory information is altered. Our results show that rate remapping can be expl! ained in terms of known mechanisms.
• Analysis of Excitatory Microcircuitry in the Medial Entorhinal Cortex Reveals Cell-Type-Specific Differences
  - Neuron (Cambridge Mass ) 68(6):1059-1066 (2010)
  Medial entorhinal cortex (MEC) plays an important role in physiological processes underlying navigation, learning, and memory. Excitatory cells in the different MEC layers project in a region-specific manner to the hippocampus. However, the intrinsic microcircuitry of the main excitatory cells in the superficial MEC layers is largely unknown. Using scanning photostimulation, we investigated the functional microcircuitry of two such cell types, stellate and pyramidal cells. We found cell-type-specific intralaminar and ascending interlaminar feedback inputs. The ascending interlaminar inputs display distinct organizational principles depending on the cell-type and its position within the superficial lamina: the spatial spread of inputs for stellate cells is narrower than for pyramidal cells, while inputs to pyramidal cells in layer 3, but not in layer 2, exhibit an asymmetric offset to the medial side of the cell's main axis. Differential laminar sources of excitatory in! puts might contribute to the functional diversity of stellate and pyramidal cells.
• Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration
  - Neuron (Cambridge Mass ) 68(6):1067-1081 (2010)
  The microtubule-associated protein tau accumulates in Alzheimer's and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mistargeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. These dat! a establish that the locus of early synaptic malfunction caused by tau resides in dendritic spines.
• Hippocampal AMPA Receptor Gating Controlled by Both TARP and Cornichon Proteins
  - Neuron (Cambridge Mass ) 68(6):1082-1096 (2010)
  Transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon proteins (CNIH-2/3) independently modulate AMPA receptor trafficking and gating. However, the potential for interactions of these subunits within an AMPA receptor complex is unknown. Here, we find that TARPs γ-4, γ-7, and γ-8, but not γ-2, γ-3, or γ-5, cause AMPA receptors to "resensitize" upon continued glutamate application. With γ-8, resensitization occurs with all GluA subunit combinations; however, γ-8-containing hippocampal neurons do not display resensitization. In recombinant systems, CNIH-2 abrogates γ-8-mediated resensitization and modifies AMPA receptor pharmacology and gating to match that of hippocampal neurons. In hippocampus, γ-8 and CNIH-2 associate in postsynaptic densities and CNIH-2 protein levels are markedly diminished in γ-8 knockout mice. Manipulating neuronal CNIH-2 levels modulates the electrophysiological properties of extrasynaptic and synaptic γ-8-containin! g AMPA receptors. Thus, γ-8 and CNIH-2 functionally interact with common hippocampal AMPA receptor complexes to modulate synergistically kinetics and pharmacology.
• Vesicular ATPase Inserted into the Plasma Membrane of Motor Terminals by Exocytosis Alkalinizes Cytosolic pH and Facilitates Endocytosis
  - Neuron (Cambridge Mass ) 68(6):1097-1108 (2010)
  Key components of vesicular neurotransmitter release, such as Ca2+ influx and membrane recycling, are affected by cytosolic pH. We measured the pH-sensitive fluorescence of Yellow Fluorescent Protein transgenically expressed in mouse motor nerve terminals, and report that Ca2+ influx elicited by action potential trains (12.5–100 Hz) evokes a biphasic pH change: a brief acidification (13 nM average peak increase in [H+]), followed by a prolonged alkalinization (30 nM peak decrease in [H+]) that outlasts the stimulation train. The alkalinization is selectively eliminated by blocking vesicular exocytosis with botulinum neurotoxins, and is prolonged by the endocytosis-inhibitor dynasore. Blocking H+ pumping by vesicular H+-ATPase (with folimycin or bafilomycin) suppresses stimulation-induced alkalinization and reduces endocytotic uptake of FM1-43. These results suggest that H+-ATPase, known to transfer cytosolic H+ into prefused vesicles, continues to extrude cytosolic H! + after being exocytotically incorporated into the plasma membrane. The resulting cytosolic alkalinization may facilitate vesicular endocytosis.
• Presynaptic NMDARs in the Hippocampus Facilitate Transmitter Release at Theta Frequency
  - Neuron (Cambridge Mass ) 68(6):1109-1127 (2010)
  A rise in [Ca2+]i provides the trigger for neurotransmitter release at neuronal boutons. We have used confocal microscopy and Ca2+ sensitive dyes to directly measure the action potential-evoked [Ca2+]i in the boutons of Schaffer collaterals. This reveals that the trial-by-trial amplitude of the evoked Ca2+ transient is bimodally distributed. We demonstrate that "large" Ca2+ transients occur when presynaptic NMDA receptors are activated following transmitter release. Presynaptic NMDA receptor activation proves critical in producing facilitation of transmission at theta frequencies. Because large Ca2+ transients "report" transmitter release, their frequency on a trial-by-trial basis can be used to estimate the probability of release, pr. We use this novel estimator to show that pr increases following the induction of long-term potentiation.
• Homeostatic Scaling Requires Group I mGluR Activation Mediated by Homer1a
  - Neuron (Cambridge Mass ) 68(6):1128-1142 (2010)
  Homeostatic scaling is a non-Hebbian form of neural plasticity that maintains neuronal excitability and informational content of synaptic arrays in the face of changes of network activity. Here, we demonstrate that homeostatic scaling is dependent on group I metabotropic glutamate receptor activation that is mediated by the immediate early gene Homer1a. Homer1a is transiently upregulated during increases in network activity and evokes agonist-independent signaling of group I mGluRs that scales down the expression of synaptic AMPA receptors. Homer1a effects are dynamic and play a role in the induction of scaling. Similar to mGluR-LTD, Homer1a-dependent scaling involves a reduction of tyrosine phosphorylation of GluA2 (GluR2), but is distinct in that it exploits a unique signaling property of group I mGluR to confer cell-wide, agonist-independent activation of the receptor. These studies reveal an elegant interplay of mechanisms that underlie Hebbian and non-Hebbian plas! ticity.
• Local Presynaptic Activity Gates Homeostatic Changes in Presynaptic Function Driven by Dendritic BDNF Synthesis
  - Neuron (Cambridge Mass ) 68(6):1143-1158 (2010)
  Homeostatic synaptic plasticity is important for maintaining stability of neuronal function, but heterogeneous expression mechanisms suggest that distinct facets of neuronal activity may shape the manner in which compensatory synaptic changes are implemented. Here, we demonstrate that local presynaptic activity gates a retrograde form of homeostatic plasticity induced by blockade of AMPA receptors (AMPARs) in cultured hippocampal neurons. We show that AMPAR blockade produces rapid (<3 hr) protein synthesis-dependent increases in both presynaptic and postsynaptic function and that the induction of presynaptic, but not postsynaptic, changes requires coincident local activity in presynaptic terminals. This "state-dependent" modulation of presynaptic function requires postsynaptic release of brain-derived neurotrophic factor (BDNF) as a retrograde messenger, which is locally synthesized in dendrites in response to AMPAR blockade. Taken together, our results reveal a lo! cal crosstalk between active presynaptic terminals and postsynaptic signaling that dictates the manner by which homeostatic plasticity is implemented at synapses.
• Role of ACh-GABA Cotransmission in Detecting Image Motion and Motion Direction
  - Neuron (Cambridge Mass ) 68(6):1159-1172 (2010)
  Starburst amacrine cells (SACs) process complex visual signals in the retina using both acetylcholine (ACh) and gamma-aminobutyric acid (GABA), but the synaptic organization and function of ACh-GABA corelease remain unclear. Here, we show that SACs make cholinergic synapses onto On-Off direction-selective ganglion cells (DSGCs) from all directions but make GABAergic synapses onto DSGCs only from the null direction. ACh and GABA were released differentially in a Ca2+ level-specific manner, suggesting the two transmitters were released from different vesicle populations. Despite the symmetric cholinergic connection, the light-evoked cholinergic input to a DSGC, detected at both light onset and offset, was motion- and direction-sensitive. This input was facilitated by two-spot apparent motion in the preferred direction but supressed in the null direction, presumably by a GABAergic mechnism. The results revealed a high level of synaptic intricacy in the starburst circuit a! nd suggested differential, yet synergistic, roles of ACh-GABA cotransmission in motion sensitivity and direction selectivity.
• Functional Organization of a Neural Network for Aversive Olfactory Learning in Caenorhabditis elegans
  - Neuron (Cambridge Mass ) 68(6):1173-1186 (2010)
  Many animals use their olfactory systems to learn to avoid dangers, but how neural circuits encode naive and learned olfactory preferences, and switch between those preferences, is poorly understood. Here, we map an olfactory network, from sensory input to motor output, which regulates the learned olfactory aversion of Caenorhabditis elegans for the smell of pathogenic bacteria. Naive animals prefer smells of pathogens but animals trained with pathogens lose this attraction. We find that two different neural circuits subserve these preferences, with one required for the naive preference and the other specifically for the learned preference. Calcium imaging and behavioral analysis reveal that the naive preference reflects the direct transduction of the activity of olfactory sensory neurons into motor response, whereas the learned preference involves modulations to signal transduction to downstream neurons to alter motor response. Thus, two different neural circuits regu! late a behavioral switch between naive and learned olfactory preferences.
• Membrane Potential Synchrony in Primary Visual Cortex during Sensory Stimulation
  - Neuron (Cambridge Mass ) 68(6):1187-1201 (2010)
  When the primary visual cortex (V1) is activated by sensory stimulation, what is the temporal correlation between the synaptic inputs to nearby neurons? This question underlies the origin of correlated activity, the mechanism of how visually evoked activity emerges and propagates in cortical circuits, and the relationship between spontaneous and evoked activity. Here, we have recorded membrane potential from pairs of V1 neurons in anesthetized cats and found that visual stimulation suppressed low-frequency membrane potential synchrony (0–10 Hz), and often increased synchrony at high frequencies (20–80 Hz). The increase in high-frequency synchrony occurred for neurons with similar orientation preferences and for neurons with different orientation preferences and occurred for a wide range of stimulus orientations. Thus, while only a subset of neurons spike in response to visual stimulation, a far larger proportion of the circuit is correlated with spiking activity th! rough subthreshold, high-frequency synchronous activity that crosses functional domains.
• Bassoon and the Synaptic Ribbon Organize Ca2+ Channels and Vesicles to Add Release Sites and Promote Refilling
  - Neuron (Cambridge Mass ) 68(6):1202 (2010)