Latest Articles Include:
- Live or Let Die: CCM2 Provides the Link
- Neuron 63(5):559-560 (2009)
TrkA receptors are well known for promoting neuronal cell survival. However, in some neuroblastic tumors, TrkA activation can instead induce apoptosis. In this issue of Neuron, Harel et al. identify CCM2 as a mediator of TrkA-dependent cell death, suggesting that CCM2 is a distinctive type of tumor suppressor that modulates tyrosine kinase signaling.
- It's In My Eyes, but It Doesn't Look that Way to Me
- Neuron 63(5):561-563 (2009)
In this issue of Neuron, Hannula and Ranganath provide striking evidence that hippocampal activity predicts eye movements that reveal memory for the past even when participants' overt memory decisions are in error. Their findings bear on an ongoing debate about the relationship between mnemonic awareness and hippocampal function.
- Nicotine's Allure
- Neuron 63(5):564-565 (2009)
Both conscious and unconscious memory mechanisms contribute to the rewarding effects of nicotine and other drugs of abuse. In this issue of Neuron, Tang and Dani use in vivo measures of synaptic plasticity in freely moving mice to link nicotine-induced dopamine release in hippocampus to LTP induction and behavioral reinforcement.
- A New Ion Channel Blooms at the Synapse
- Neuron 63(5):566-567 (2009)
A new study by Yao et al. in the current issue of Cell proposes that a novel vesicular protein, dubbed Flower, regulates endocytosis by controlling presynaptic Ca2+ levels. This finding is intriguing not only for its implications for vesicle cycling, but also for the multitude of Ca2+-dependent processes at play in presynaptic nerve terminals.
- Intention, Action Planning, and Decision Making in Parietal-Frontal Circuits
- Neuron 63(5):568-583 (2009)
The posterior parietal cortex and frontal cortical areas to which it connects are responsible for sensorimotor transformations. This review covers new research on four components of this transformation process: planning, decision making, forward state estimation, and relative-coordinate representations. These sensorimotor functions can be harnessed for neural prosthetic operations by decoding intended goals (planning) and trajectories (forward state estimation) of movements as well as higher cortical functions related to decision making and potentially the coordination of multiple body parts (relative-coordinate representations).
- CCM2 Mediates Death Signaling by the TrkA Receptor Tyrosine Kinase
- Neuron 63(5):585-591 (2009)
The TrkA receptor tyrosine kinase is crucial for differentiation and survival of nerve-growth-factor-dependent neurons. Paradoxically, TrkA also induces cell death in pediatric tumor cells of neural origin, via an unknown mechanism. Here, we show that CCM2, a gene product associated with cerebral cavernous malformations, interacts with the juxtamembrane region of TrkA via its phosphotyrosine binding (PTB) domain and mediates TrkA-induced death in diverse cell types. Both the PTB and Karet domains of CCM2 are required for TrkA-dependent cell death, such that the PTB domain determines the specificity of the interaction, and the Karet domain links to death pathways. Downregulation of CCM2 in medulloblastoma or neuroblastoma cells attenuates TrkA-dependent death. Combined high expression levels of CCM2 and TrkA are correlated with long-term survival in a large cohort of human neuroblastoma patients. Thus, CCM2 is a key mediator of TrkA-dependent cell death in pediatric neu! roblastic tumors.
- The Eyes Have It: Hippocampal Activity Predicts Expression of Memory in Eye Movements
- Neuron 63(5):592-599 (2009)
Although there is widespread agreement that the hippocampus is critical for explicit episodic memory retrieval, it is controversial whether this region can also support indirect expressions of relational memory when explicit retrieval fails. Here, using functional magnetic resonance imaging (fMRI) with concurrent indirect, eye-movement-based memory measures, we obtained evidence that hippocampal activity predicted expressions of relational memory in subsequent patterns of viewing, even when explicit, conscious retrieval failed. Additionally, activity in the lateral prefrontal cortex and functional connectivity between the hippocampus and prefrontal cortex were greater for correct than for incorrect trials. Together, these results suggest that hippocampal activity can support the expression of relational memory even when explicit retrieval fails and that recruitment of a broader cortical network may be required to support explicit associative recognition.
- Polycomb Limits the Neurogenic Competence of Neural Precursor Cells to Promote Astrogenic Fate Transition
- Neuron 63(5):600-613 (2009)
During neocortical development, neural precursor cells (NPCs, or neural stem cells) produce neurons first and astrocytes later. Although the timing of the fate switch from neurogenic to astrogenic is critical for determining the number of neurons, the mechanisms are not fully understood. Here, we show that the polycomb group complex (PcG) restricts neurogenic competence of NPCs and promotes the transition of NPC fate from neurogenic to astrogenic. Inactivation of PcG by knockout of the Ring1B or Ezh2 gene or Eed knockdown prolonged the neurogenic phase of NPCs and delayed the onset of the astrogenic phase. Moreover, PcG was found to repress the promoter of the proneural gene neurogenin1 in a developmental-stage-dependent manner. These results demonstrate a role of PcG: the temporal regulation of NPC fate.
- LIG Family Receptor Tyrosine Kinase-Associated Proteins Modulate Growth Factor Signals during Neural Development
- Neuron 63(5):614-627 (2009)
Genome-wide screens were performed to identify transmembrane proteins that mediate axonal growth, guidance and target field innervation of somatosensory neurons. One gene, Linx (alias Islr2), encoding a leucine-rich repeat and immunoglobulin (LIG) family protein, is expressed in a subset of developing sensory and motor neurons. Domain and genomic structures of Linx and other LIG family members suggest that they are evolutionarily related to Trk receptor tyrosine kinases (RTKs). Several LIGs, including Linx, are expressed in subsets of somatosensory and motor neurons, and select members interact with TrkA and Ret RTKs. Moreover, axonal projection defects in mice harboring a null mutation in Linx resemble those in mice lacking Ngf, TrkA, and Ret. In addition, Linx modulates NGF–TrkA- and GDNF-GFRα1/Ret-mediated axonal extension in cultured sensory and motor neurons, respectively. These findings show that LIGs physically interact with RTKs and modulate their activities! to control axonal extension, guidance and branching.
- Neuroligin 2 Drives Postsynaptic Assembly at Perisomatic Inhibitory Synapses through Gephyrin and Collybistin
- Neuron 63(5):628-642 (2009)
In the mammalian CNS, each neuron typically receives thousands of synaptic inputs from diverse classes of neurons. Synaptic transmission to the postsynaptic neuron relies on localized and transmitter-specific differentiation of the plasma membrane with postsynaptic receptor, scaffolding, and adhesion proteins accumulating in precise apposition to presynaptic sites of transmitter release. We identified protein interactions of the synaptic adhesion molecule neuroligin 2 that drive postsynaptic differentiation at inhibitory synapses. Neuroligin 2 binds the scaffolding protein gephyrin through a conserved cytoplasmic motif and functions as a specific activator of collybistin, thus guiding membrane tethering of the inhibitory postsynaptic scaffold. Complexes of neuroligin 2, gephyrin and collybistin are sufficient for cell-autonomous clustering of inhibitory neurotransmitter receptors. Deletion of neuroligin 2 in mice perturbs GABAergic and glycinergic synaptic transmission! and leads to a loss of postsynaptic specializations specifically at perisomatic inhibitory synapses.
- NCS-1 in the Dentate Gyrus Promotes Exploration, Synaptic Plasticity, and Rapid Acquisition of Spatial Memory
- Neuron 63(5):643-656 (2009)
The molecular underpinnings of exploration and its link to learning and memory remain poorly understood. Here we show that inducible, modest overexpression of neuronal calcium sensor 1 (Ncs1) selectively in the adult murine dentate gyrus (DG) promotes a specific form of exploratory behavior. The mice also display a selective facilitation of long-term potentiation (LTP) in the medial perforant path and a selective enhancement in rapid-acquisition spatial memory, phenotypes that are reversed by direct application of a cell-permeant peptide (DNIP) designed to interfere with NCS-1 binding to the dopamine type-2 receptor (D2R). Moreover, the DNIP and the D2R-selective antagonist L-741,626 attenuated exploratory behavior, DG LTP, and spatial memory in control mice. These data demonstrate a role for NCS-1 and D2R in DG plasticity and provide insight for understanding how the DG contributes to the origin of exploration and spatial memory acquisition.
- Differences in Cortical versus Subcortical GABAergic Signaling: A Candidate Mechanism of Electroclinical Uncoupling of Neonatal Seizures
- Neuron 63(5):657-672 (2009)
Electroclinical uncoupling of neonatal seizures refers to electrographic seizure activity that is not clinically manifest. Uncoupling increases after treatment with Phenobarbital, which enhances the GABAA receptor (GABAAR) conductance. The effects of GABAAR activation depend on the intracellular Cl− concentration ([Cl−]i) that is determined by the inward Cl− transporter NKCC1 and the outward Cl− transporter KCC2. Differential maturation of Cl− transport observed in cortical versus subcortical regions should alter the efficacy of GABA-mediated inhibition. In perinatal rat pups, most thalamic neurons maintained low [Cl−]i and were inhibited by GABA. Phenobarbital suppressed thalamic seizure activity. Most neocortical neurons maintained higher [Cl−]i, and were excited by GABAAR activation. Phenobarbital had insignificant anticonvulsant responses in the neocortex until NKCC1 was blocked. Regional differences in the ontogeny of Cl− transport may thus explain! why seizure activity in the cortex is not suppressed by anticonvulsants that block the transmission of seizure activity through subcortical networks.
- Dopamine Enables In Vivo Synaptic Plasticity Associated with the Addictive Drug Nicotine
- Neuron 63(5):673-682 (2009)
Addictive drugs induce a dopamine signal that contributes to the initiation of addiction, and the dopamine signal influences drug-associated memories that perpetuate drug use. The addiction process shares many commonalities with the synaptic plasticity mechanisms normally attributed to learning and memory. Environmental stimuli repeatedly linked to addictive drugs become learned associations, and those stimuli come to elicit memories or sensations that motivate continued drug use. Applying in vivo recording techniques to freely moving mice, we show that physiologically relevant concentrations of the addictive drug nicotine directly cause in vivo hippocampal synaptic potentiation of the kind that underlies learning and memory. The drug-induced long-term synaptic plasticity required a local hippocampal dopamine signal. Disrupting general dopamine signaling prevented the nicotine-induced synaptic plasticity and conditioned place preference. These results suggest that dopa! minergic signaling serves as a functional label of salient events by enabling and scaling synaptic plasticity that underlies drug-induced associative memory.
- Temporal Framing of Thalamic Relay-Mode Firing by Phasic Inhibition during the Alpha Rhythm
- Neuron 63(5):683-696 (2009)
Several aspects of perception, particularly those pertaining to vision, are closely linked to the occipital alpha (α) rhythm. However, how the α rhythm relates to the activity of neurons that convey primary visual information is unknown. Here we show that in behaving cats, thalamocortical neurons in the lateral geniculate nucleus (LGN) that operate in a conventional relay-mode form two groups where the cumulative firing is subject to a cyclic suppression that is centered on the negative α rhythm peak in one group and on the positive peak in the other. This leads to an effective temporal framing of relay-mode output and results from phasic inhibition from LGN interneurons, which in turn are rhythmically excited by thalamocortical neurons that exhibit high-threshold bursts. These results provide a potential cellular substrate for linking the α rhythm to perception and further underscore the central role of inhibition in controlling spike timing during cognitively rel! evant brain oscillations.
- Recollection, Familiarity, and Cortical Reinstatement: A Multivoxel Pattern Analysis
- Neuron 63(5):697-708 (2009)
Episodic memory retrieval is thought to involve reinstatement of the neurocognitive processes engaged when an episode was encoded. Prior fMRI studies and computational models have suggested that reinstatement is limited to instances in which specific episodic details are recollected. We used multivoxel pattern-classification analyses of fMRI data to investigate how reinstatement is associated with different memory judgments, particularly those accompanied by recollection versus a feeling of familiarity (when recollection is absent). Classifiers were trained to distinguish between brain activity patterns associated with different encoding tasks and were subsequently applied to recognition-related fMRI data to determine the degree to which patterns were reinstated. Reinstatement was evident during both recollection- and familiarity-based judgments, providing clear evidence that reinstatement is not sufficient for eliciting a recollective experience. The findings are inte! rpreted as support for a continuous, recollection-related neural signal that has been central to recent debate over the nature of recognition memory processes.
- GOSPEL: A Neuroprotective Protein that Binds to GAPDH upon S-Nitrosylation
- Neuron 63(5):709 (2009)
- A Role for SNAP25 in Internalization of Kainate Receptors and Synaptic Plasticity
- Neuron 63(5):709 (2009)