Hot off the presses! Jan 28 Neuron

The Jan 28 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:

• Kalzium Ist Nicht Alles
  - Neuron 65(2):143-144 (2010)
  Elevation of cerebral Mg2+ with a novel orally delivered ionophore, magnesium threonate, enhances cognition in young and old rats over a 12-24 day treatment interval, as outlined in a paper by Slutsky et al. in this issue of Neuron. Despite both Mg2+ and Zn2+ blocking the NMDA receptor channel, sustained extracellular Mg2+ elevation mimics sustained synaptic Zn2+ concentrations by increasing hippocampal NR2B expression and bouton density.
• Location, Location, Location: Contrasting Roles of Synaptic and Extrasynaptic NMDA Receptors in Huntington's Disease
  - Neuron 65(2):145-147 (2010)
  Abnormally enhanced N-methyl-D-aspartate (NMDA) receptor function is implicated in Huntington's disease (HD). In this issue of Neuron and a recent issue of Nature Medicine, an abnormal balance between the activity of NMDA receptors at synaptic (prosurvival) and extrasynaptic (proapoptotic) sites has been uncovered in a cellular and a mouse model of HD.
• Excitatory Neuromodulator Reduces Dopamine Release, Enhancing Prolactin Secretion
  - Neuron 65(2):147-149 (2010)
  Hypothalamic dopamine neurons inhibit pituitary prolactin secretion. In this issue of Neuron, Lyons et al. provide evidence for a novel model, whereby the excitatory neuropeptide TRH depolarizes gap-junction-coupled dopamine neurons, leading to a shift in the population pattern of action potentials from phasic burst firing to regular tonic firing, hypothetically reducing dopamine release while increasing total spike number.
• Eye Smarter than Scientists Believed: Neural Computations in Circuits of the Retina
  - Neuron 65(2):150-164 (2010)
  We rely on our visual system to cope with the vast barrage of incoming light patterns and to extract features from the scene that are relevant to our well-being. The necessary reduction of visual information already begins in the eye. In this review, we summarize recent progress in understanding the computations performed in the vertebrate retina and how they are implemented by the neural circuitry. A new picture emerges from these findings that helps resolve a vexing paradox between the retina's structure and function. Whereas the conventional wisdom treats the eye as a simple prefilter for visual images, it now appears that the retina solves a diverse set of specific tasks and provides the results explicitly to downstream brain areas.
• Enhancement of Learning and Memory by Elevating Brain Magnesium
  - Neuron 65(2):165-177 (2010)
  Learning and memory are fundamental brain functions affected by dietary and environmental factors. Here, we show that increasing brain magnesium using a newly developed magnesium compound (magnesium-L-threonate, MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. The pattern completion ability was also improved in aged rats. MgT-treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of hippocampus that were correlated with memory improvement. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced. Our findings suggest th at an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.
• Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice
  - Neuron 65(2):178-190 (2010)
  N-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative diseas e. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice.
• Hook3 Interacts with PCM1 to Regulate Pericentriolar Material Assembly and the Timing of Neurogenesis
  - Neuron 65(2):191-203 (2010)
  Centrosome functions are important in multiple brain developmental processes. Proper functioning of the centrosome relies on assembly of protein components into the pericentriolar material. This dynamic assembly is mediated by the trafficking of pericentriolar satellites, which are comprised of centrosomal proteins. Here we demonstrate that trafficking of pericentriolar satellites requires the interaction between Hook3 and Pericentriolar Material 1 (PCM1). Hook3, previously shown to link the centrosome and the nucleus in C. elegans, is recruited to pericentriolar satellites through interaction with PCM1, a protein associated with schizophrenia. Disruption of the Hook3-PCM1 interaction in vivo impairs interkinetic nuclear migration, a featured behavior of embryonic neural progenitors. This in turn leads to overproduction of neurons and premature depletion of the neural progenitor pool in the developing neocortex. These results underscore the importance of centrosomal ass embly in neurogenesis and provide potential insights into the etiology of brain developmental diseases related to the centrosome dysfunction.
• Ephexin1 Is Required for Structural Maturation and Neurotransmission at the Neuromuscular Junction
  - Neuron 65(2):204-216 (2010)
  The maturation of neuromuscular junctions (NMJs) requires the topological transformation of postsynaptic acetylcholine receptor (AChR)-containing structures from a simple plaque to an elaborate structure composed of pretzel-like branches. This maturation process results in the precise apposition of the presynaptic and postsynaptic specializations. However, little is known about the molecular mechanisms underlying the plaque-to-pretzel transition of AChR clusters. In this study, we identify an essential role for the RhoGEF ephexin1 in the maturation of AChR clusters. Adult ephexin1−/− mice exhibit severe muscle weakness and impaired synaptic transmission at the NMJ. Intriguingly, when ephexin1 expression is deficient in vivo, the NMJ fails to mature into the pretzel-like shape, and such abnormalities can be rescued by re-expression of ephexin1. We further demonstrate that ephexin1 regulates the stability of AChR clusters in a RhoA-dependent manner. Taken together, ou r findings reveal an indispensible role for ephexin1 in regulating the structural maturation and neurotransmission of NMJs.
• Synchronized Network Oscillations in Rat Tuberoinfundibular Dopamine Neurons: Switch to Tonic Discharge by Thyrotropin-Releasing Hormone
  - Neuron 65(2):217-229 (2010)
  The pituitary hormone, prolactin, triggers lactation in nursing mothers. Under nonlactating conditions, prolactin secretion is suppressed by powerful inhibition from hypothalamic tuberoinfundibular dopamine (TIDA) neurons. Although firing pattern has been suggested as integral to neuroendocrine control, the electrical behavior of TIDA cells remains unknown. We demonstrate that rat TIDA neurons discharge rhythmically in a robust 0.05 Hz oscillation. The oscillation is phase locked between neurons, and while it persists during chemical synaptic transmission blockade, it is abolished by gap junction antagonists. Thyrotropin-releasing hormone (TRH) potently stimulates prolactin release, an effect assumed to take place in the pituitary. In TIDA cells, TRH caused a transition from phasic to tonic firing through combined pre- and postsynaptic effects. These findings suggest a model for prolactin regulation where a TIDA network switch from oscillations to sustained discharge co nverts dopamine from an antagonist at high concentrations to a functional agonist as dopamine output from the network decreases.
• Pathway-Specific Feedforward Circuits between Thalamus and Neocortex Revealed by Selective Optical Stimulation of Axons
  - Neuron 65(2):230-245 (2010)
  Thalamocortical and corticothalamic pathways mediate bidirectional communication between the thalamus and neocortex. These pathways are entwined, making their study challenging. Here we used lentiviruses to express channelrhodopsin-2 (ChR2), a light-sensitive cation channel, in either thalamocortical or corticothalamic projection cells. Infection occurred only locally, but efferent axons and their terminals expressed ChR2 strongly, allowing selective optical activation of each pathway. Laser stimulation of ChR2-expressing thalamocortical axons/terminals evoked robust synaptic responses in cortical excitatory cells and fast-spiking (FS) inhibitory interneurons, but only weak responses in somatostatin-containing interneurons. Strong FS cell activation led to feedforward inhibition in all cortical neuron types, including FS cells. Corticothalamic stimulation excited thalamic relay cells and inhibitory neurons of the thalamic reticular nucleus (TRN). TRN activation triggere d inhibition in relay cells but not in TRN neurons. Thus, a major difference between thalamocortical and corticothalamic processing was the extent to which feedforward inhibitory neurons were themselves engaged by feedforward inhibition.
• Critical Period Plasticity Matches Binocular Orientation Preference in the Visual Cortex
  - Neuron 65(2):246-256 (2010)
  Changes of ocular dominance in the visual cortex can be induced by visual manipulations during a critical period in early life. However, the role of critical period plasticity in normal development is unknown. Here we show that at the onset of this time window, the preferred orientations of individual cortical cells in the mouse are mismatched through the two eyes and the mismatch decreases and reaches adult levels by the end of the period. Deprivation of visual experience during this period irreversibly blocks the binocular matching of orientation preference, but has no effect in adulthood. The critical period of binocular matching can be delayed by long-term visual deprivation from birth, like that of ocular dominance plasticity. These results demonstrate that activity-dependent changes induced by normal visual experience during the well-studied critical period serve to match eye-specific inputs in the cortex, thus revealing a physiological role for critical period pl asticity during normal development.
• Synchronized Activity between the Ventral Hippocampus and the Medial Prefrontal Cortex during Anxiety
  - Neuron 65(2):257-269 (2010)
  The ventral hippocampus, unlike its dorsal counterpart, is required for anxiety-like behavior. The means by which it acts are unknown. We hypothesized that the hippocampus synchronizes with downstream targets that influence anxiety, such as the medial prefrontal cortex (mPFC). To test this hypothesis, we recorded mPFC and hippocampal activity in mice exposed to two anxiogenic arenas. Theta-frequency activity in the mPFC and ventral, but not dorsal, hippocampus was highly correlated at baseline, and this correlation increased in both anxiogenic environments. Increases in mPFC theta power predicted avoidance of the aversive compartments of each arena and were larger in serotonin 1A receptor knockout mice, a genetic model of increased anxiety-like behavior. These results suggest a role for theta-frequency synchronization between the ventral hippocampus and the mPFC in anxiety. They are consistent with the notion that such synchronization is a general mechanism by which the hippocampus communicates with downstream structures of behavioral relevance.
• A Disynaptic Relay from Superior Colliculus to Dorsal Stream Visual Cortex in Macaque Monkey
  - Neuron 65(2):270-279 (2010)
  The superior colliculus (SC) is the first station in a subcortical relay of retinal information to extrastriate visual cortex. Ascending SC projections pass through pulvinar and LGN on their way to cortex, but it is not clear how many synapses are required to complete these circuits or which cortical areas are involved. To examine this relay directly, we injected transynaptic rabies virus into several extrastriate visual areas. We observed disynaptically labeled cells in superficial, retino-recipient SC layers from injections in dorsal stream areas MT and V3, but not the earliest extrastriate area, V2, nor ventral stream area V4. This robust SC-dorsal stream pathway is most likely relayed through the inferior pulvinar and can provide magnocellular-like sensory inputs necessary for motion perception and the computation of orienting movements. Furthermore, by circumventing primary visual cortex, this pathway may also underlie the remaining visual capacities associated wit h blindsight.
• Enhanced Brain Correlations during Rest Are Related to Memory for Recent Experiences
  - Neuron 65(2):280-290 (2010)
  Long-term storage of episodic memories is hypothesized to result from the off-line transfer of information from the hippocampus to neocortex, allowing a hippocampal-independent cortical representation to emerge. However, off-line hippocampal-cortical interactions have not been demonstrated to be linked with long-term memory. Here, using functional magnetic resonance imaging, we examined if hippocampal-cortical BOLD correlations during rest following an associative encoding task are related to later associative memory performance. Our data show enhanced functional connectivity between the hippocampus and a portion of the lateral occipital complex (LO) during rest following a task with high subsequent memory compared to pretask baseline resting connectivity. This effect is not seen during rest following a task with poor subsequent memory. Furthermore, the magnitude of hippocampal-LO correlations during posttask rest predicts individual differences in later associative mem ory. These results demonstrate the importance of postexperience resting brain correlations for memory for recent experiences. 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 (23044 K)