Hot off the presses! May 12 Neuron

The May 12 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:

• Are Polyglutamine Diseases Expanding?
  - Neuron 70(3):377-378 (2011)
  It remains a matter of speculation as to whether the sense CUG-containing RNA and/or the antisense CAG-encoding polyglutamine peptide serves as the pathogenic moiety in Huntington's disease like-2 (HDL2). In this issue of Neuron, Wilburn et al. show that in a HDL2 mouse model, the polyglutamine peptide drives disease progression.
• Transsynaptic Coordination of Presynaptic and Postsynaptic Modifications underlying Enduring Synaptic Plasticity
  - Neuron 70(3):379-381 (2011)
  Neurexins and neuroligins are cell adhesion molecules that form transsynaptic interactions. In this issue of Neuron, Choi et al. report that neurexin-neuroligin signaling plays a critical role in functional and structural synaptic plasticity underlying memory formation in Aplysia.
• Making Choices between Rules or between Actions
  - Neuron 70(3):382-384 (2011)
  A new study by Klaes et al. in this issue of Neuron shows that the brain can simultaneously apply two rules to the same sensory information in order to specify two parallel potential action goals, which then compete for execution in the sensorimotor system.
• GABAA Receptor Trafficking-Mediated Plasticity of Inhibitory Synapses
  - Neuron 70(3):385-409 (2011)
  Proper developmental, neural cell-type-specific, and activity-dependent regulation of GABAergic transmission is essential for virtually all aspects of CNS function. The number of GABAA receptors in the postsynaptic membrane directly controls the efficacy of GABAergic synaptic transmission. Thus, regulated trafficking of GABAA receptors is essential for understanding brain function in both health and disease. Here we summarize recent progress in the understanding of mechanisms that allow dynamic adaptation of cell surface expression and postsynaptic accumulation and function of GABAA receptors. This includes activity-dependent and cell-type-specific changes in subunit gene expression, assembly of subunits into receptors, as well as exocytosis, endocytic recycling, diffusion dynamics, and degradation of GABAA receptors. In particular, we focus on the roles of receptor-interacting proteins, scaffold proteins, synaptic adhesion proteins, and enzymes that regulate the traff! icking and function of receptors and associated proteins. In addition, we review neuropeptide signaling pathways that affect neural excitability through changes in GABAAR trafficking.
• The Many Faces of Tau
  - Neuron 70(3):410-426 (2011)
  While the microtubule-binding capacity of the protein tau has been known for many years, new functions of tau in signaling and cytoskeletal organization have recently emerged. In this review, we highlight these functions and the potential roles of tau in neurodegenerative disease. We also discuss the therapeutic potential of drugs targeting various aspects of tau biology.
• An Antisense CAG Repeat Transcript at JPH3 Locus Mediates Expanded Polyglutamine Protein Toxicity in Huntington's Disease-like 2 Mice
  - Neuron 70(3):427-440 (2011)
  Huntington's disease-like-2 (HDL2) is a phenocopy of Huntington's disease caused by CTG/CAG repeat expansion at the Junctophilin-3 (JPH3) locus. The mechanisms underlying HDL2 pathogenesis remain unclear. Here we developed a BAC transgenic mouse model of HDL2 (BAC-HDL2) that exhibits progressive motor deficits, selective neurodegenerative pathology, and ubiquitin-positive nuclear inclusions (NIs). Molecular analyses reveal a promoter at the transgene locus driving the expression of a CAG repeat transcript (HDL2-CAG) from the strand antisense to JPH3, which encodes an expanded polyglutamine (polyQ) protein. Importantly, BAC-HDL2 mice, but not control BAC mice, accumulate polyQ-containing NIs in a pattern strikingly similar to those in the patients. Furthermore, BAC mice with genetic silencing of the expanded CUG transcript still express HDL2-CAG transcript and manifest polyQ pathogenesis. Finally, studies of HDL2 mice and patients revealed CBP sequestration into NIs and! evidence for interference of CBP-mediated transcriptional activation. These results suggest overlapping polyQ-mediated pathogenic mechanisms in HD and HDL2.
• Mechanistic Logic Underlying the Axonal Transport of Cytosolic Proteins
  - Neuron 70(3):441-454 (2011)
  Proteins vital to presynaptic function are synthesized in the neuronal perikarya and delivered into synapses via two modes of axonal transport. While membrane-anchoring proteins are conveyed in fast axonal transport via motor-driven vesicles, cytosolic proteins travel in slow axonal transport via mechanisms that are poorly understood. We found that in cultured axons, populations of cytosolic proteins tagged to photoactivatable GFP (PAGFP) move with a slow motor-dependent anterograde bias distinct from both vesicular trafficking and diffusion of untagged PAGFP. The overall bias is likely generated by an intricate particle kinetics involving transient assembly and short-range vectorial spurts. In vivo biochemical studies reveal that cytosolic proteins are organized into higher order structures within axon-enriched fractions that are largely segregated from vesicles. Data-driven biophysical modeling best predicts a scenario where soluble molecules dynamically assemble int! o mobile supramolecular structures. We propose a model where cytosolic proteins are transported by dynamically assembling into multiprotein complexes that are directly/indirectly conveyed by motors.
• Activity-Dependent Transcription of BDNF Enhances Visual Acuity during Development
  - Neuron 70(3):455-467 (2011)
  In the developing Xenopus tadpole, conditioning with 20 min of visual stimulation leads to increased proBDNF protein levels in the tectum measured 4 hr later. Following conditioning, the ability to induce direction selectivity in tectal neurons, as well as both retinotectal long-term potentiation and depression, thought to underlie this phenomenon, was strongly facilitated. This facilitation was blocked by knockdown of BDNF expression in tectal neurons. Animals that had been exposed to visual conditioning and subsequently received normal visual input for 7–11 hr exhibited higher spatial frequency thresholds of tectal cell responses to counterphasing gratings than nonconditioned control animals. An improvement in visual acuity was confirmed by enhanced sensitivity to counterphasing gratings in a behavioral test. These results indicate that brief sensory stimulation, by initiating nuclear transcription and de novo protein synthesis of BDNF, can facilitate the refinemen! t of response properties in the developing visual system.
• Neurexin-Neuroligin Transsynaptic Interaction Mediates Learning-Related Synaptic Remodeling and Long-Term Facilitation in Aplysia
  - Neuron 70(3):468-481 (2011)
  Neurexin and neuroligin, which undergo heterophilic interactions with each other at the synapse, are mutated in some patients with autism spectrum disorder, a set of disorders characterized by deficits in social and emotional learning. We have explored the role of neurexin and neuroligin at sensory-to-motor neuron synapses of the gill-withdrawal reflex in Aplysia, which undergoes sensitization, a simple form of learned fear. We find that depleting neurexin in the presynaptic sensory neuron or neuroligin in the postsynaptic motor neuron abolishes both long-term facilitation and the associated presynaptic growth induced by repeated pulses of serotonin. Moreover, introduction into the motor neuron of the R451C mutation of neuroligin-3 linked to autism spectrum disorder blocks both intermediate-term and long-term facilitation. Our results suggest that activity-dependent regulation of the neurexin-neuroligin interaction may govern transsynaptic signaling required for the st! orage of long-term memory, including emotional memory that may be impaired in autism spectrum disorder.
• TRPM3 Is a Nociceptor Channel Involved in the Detection of Noxious Heat
  - Neuron 70(3):482-494 (2011)
  Transient receptor potential melastatin-3 (TRPM3) is a broadly expressed Ca2+-permeable nonselective cation channel. Previous work has demonstrated robust activation of TRPM3 by the neuroactive steroid pregnenolone sulfate (PS), but its in vivo gating mechanisms and functions remained poorly understood. Here, we provide evidence that TRPM3 functions as a chemo- and thermosensor in the somatosensory system. TRPM3 is molecularly and functionally expressed in a large subset of small-diameter sensory neurons from dorsal root and trigeminal ganglia, and mediates the aversive and nocifensive behavioral responses to PS. Moreover, we demonstrate that TRPM3 is steeply activated by heating and underlies heat sensitivity in a subset of sensory neurons. TRPM3-deficient mice exhibited clear deficits in their avoidance responses to noxious heat and in the development of inflammatory heat hyperalgesia. These experiments reveal an unanticipated role for TRPM3 as a thermosensitive noci! ceptor channel implicated in the detection of noxious heat.
• TRIP8b Splice Forms Act in Concert to Regulate the Localization and Expression of HCN1 Channels in CA1 Pyramidal Neurons
  - Neuron 70(3):495-509 (2011)
  HCN1 channel subunits, which contribute to the hyperpolarization-activated cation current (Ih), are selectively targeted to distal apical dendrites of hippocampal CA1 pyramidal neurons. Here, we addressed the importance of the brain-specific auxiliary subunit of HCN1, TRIP8b, in regulating HCN1 expression and localization. More than ten N-terminal splice variants of TRIP8b exist in brain and exert distinct effects on HCN1 trafficking when overexpressed. We found that isoform-wide disruption of the TRIP8b/HCN1 interaction caused HCN1 to be mistargeted throughout CA1 somatodendritic compartments. In contrast, HCN1 was targeted normally to CA1 distal dendrites in a TRIP8b knockout mouse that selectively lacked exons 1b and 2. Of the two remaining hippocampal TRIP8b isoforms, TRIP8b(1a-4) promoted HCN1 surface expression in dendrites, whereas TRIP8b(1a) suppressed HCN1 misexpression in axons. Thus, proper subcellular localization of HCN1 depends on its differential additiv! e and subtractive sculpting by two isoforms of a single auxiliary subunit.
• Maturation of a Recurrent Excitatory Neocortical Circuit by Experience-Dependent Unsilencing of Newly Formed Dendritic Spines
  - Neuron 70(3):510-521 (2011)
  Local recurrent excitatory circuits are ubiquitous in neocortex, yet little is known about their development or architecture. Here we introduce a quantitative technique for efficient single-cell resolution circuit mapping using 2-photon (2P) glutamate uncaging and analyze experience-dependent neonatal development of the layer 4 barrel cortex local excitatory circuit. We show that sensory experience specifically drives a 3-fold increase in connectivity at postnatal day (P) 9, producing a highly recurrent network. A profound dendritic spinogenesis occurs concurrent with the connectivity increase, but this is not experience dependent. However, in experience-deprived cortex, a much greater proportion of spines lack postsynaptic AMPA receptors (AMPARs) and synaptic connectivity via NMDA receptors (NMDARs) is the same as in normally developing cortex. Thus we describe a approach for quantitative circuit mapping and show that sensory experience sculpts an intrinsically develo! ping template network, which is based on NMDAR-only synapses, by driving AMPARs into newly formed silent spines.
• Aversion to Nicotine Is Regulated by the Balanced Activity of β4 and α5 Nicotinic Receptor Subunits in the Medial Habenula
  - Neuron 70(3):522-535 (2011)
  Nicotine dependence is linked to single nucleotide polymorphisms in the CHRNB4-CHRNA3-CHRNA5 gene cluster encoding the α3β4α5 nicotinic acetylcholine receptor (nAChR). Here we show that the β4 subunit is rate limiting for receptor activity, and that current increase by β4 is maximally competed by one of the most frequent variants associated with tobacco usage (D398N in α5). We identify a β4-specific residue (S435), mapping to the intracellular vestibule of the α3β4α5 receptor in close proximity to α5 D398N, that is essential for its ability to increase currents. Transgenic mice with targeted overexpression of Chrnb4 to endogenous sites display a strong aversion to nicotine that can be reversed by viral-mediated expression of the α5 D398N variant in the medial habenula (MHb). Thus, this study both provides insights into α3β4α5 receptor-mediated mechanisms contributing to nicotine consumption, and identifies the MHb as a critical element in the circuitry c! ontrolling nicotine-dependent phenotypes.
• Choosing Goals, Not Rules: Deciding among Rule-Based Action Plans
  - Neuron 70(3):536-548 (2011)
  In natural situations, movements are often directed toward locations different from that of the evoking sensory stimulus. Movement goals must then be inferred from the sensory cue based on rules. When there is uncertainty about the rule that applies for a given cue, planning a movement involves both choosing the relevant rule and computing the movement goal based on that rule. Under these conditions, it is not clear whether primates compute multiple movement goals based on all possible rules before choosing an action, or whether they first choose a rule and then only represent the movement goal associated with that rule. Supporting the former hypothesis, we show that neurons in the frontoparietal reach areas of monkeys simultaneously represent two different rule-based movement goals, which are biased by the monkeys' choice preferences. Apparently, primates choose between multiple behavioral options by weighing against each other the movement goals associated with each ! option.
• Perceptual Learning and Decision-Making in Human Medial Frontal Cortex
  - Neuron 70(3):549-559 (2011)
  The dominant view that perceptual learning is accompanied by changes in early sensory representations has recently been challenged. Here we tested the idea that perceptual learning can be accounted for by reinforcement learning involving changes in higher decision-making areas. We trained subjects on an orientation discrimination task involving feedback over 4 days, acquiring fMRI data on the first and last day. Behavioral improvements were well explained by a reinforcement learning model in which learning leads to enhanced readout of sensory information, thereby establishing noise-robust representations of decision variables. We find stimulus orientation encoded in early visual and higher cortical regions such as lateral parietal cortex and anterior cingulate cortex (ACC). However, only activity patterns in the ACC tracked changes in decision variables during learning. These results provide strong evidence for perceptual learning-related changes in higher order areas ! and suggest that perceptual and reward learning are based on a common neurobiological mechanism.
• Triangulating the Neural, Psychological, and Economic Bases of Guilt Aversion
  - Neuron 70(3):560-572 (2011)
  Why do people often choose to cooperate when they can better serve their interests by acting selfishly? One potential mechanism is that the anticipation of guilt can motivate cooperative behavior. We utilize a formal model of this process in conjunction with fMRI to identify brain regions that mediate cooperative behavior while participants decided whether or not to honor a partner's trust. We observed increased activation in the insula, supplementary motor area, dorsolateral prefrontal cortex (PFC), and temporal parietal junction when participants were behaving consistent with our model, and found increased activity in the ventromedial PFC, dorsomedial PFC, and nucleus accumbens when they chose to abuse trust and maximize their financial reward. This study demonstrates that a neural system previously implicated in expectation processing plays a critical role in assessing moral sentiments that in turn can sustain human cooperation in the face of temptation. 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 (23448 K)