Hot off the presses! Jan 14 Neuron

The Jan 14 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:

• Altered Function of the Serotonin 1A Autoreceptor and the Antidepressant Response
  - Neuron 65(1):1-2 (2010)
  In this issue of Neuron, Richardson-Jones et al. report on a novel genetic approach to conditionally and specifically dampen the function of the 5-HT1A autoreceptor in mice to study its role on the 5-HT system and on the antidepressant-like effect of the selective serotonin reuptake inhibitor (SSRI) fluoxetine.
• α-Synuclein at the Synaptic Gate
  - Neuron 65(1):3-4 (2010)
  Only doubling or tripling α-synuclein expression significantly increases the risk of developing Parkinson's disease. In this issue of Neuron, Nemani et al. show that this modest overexpression of α-synuclein does not lead to obvious toxicity in the near term, but impairs glutamate and dopamine release, potentially leading to broad network dysfunction and eventual pathology.
• The Dance of the Perivascular and Endothelial Cells: Mechanisms of Brain Response to Immune Signaling
  - Neuron 65(1):4-6 (2010)
  The mechanisms underlying the brain response to systemic inflammation remain unclear. In this issue of Neuron, Serrats and colleagues demonstrate that two cell types that produce prostaglandins that act on the brain, perivascular and endothelial cells, have an unexpectedly complex interaction in regulating the timing and types of brain responses that occur.
• Are the Dorsal and Ventral Hippocampus Functionally Distinct Structures?
  - Neuron 65(1):7-19 (2010)
  One literature treats the hippocampus as a purely cognitive structure involved in memory; another treats it as a regulator of emotion whose dysfunction leads to psychopathology. We review behavioral, anatomical, and gene expression studies that together support a functional segmentation into three hippocampal compartments: dorsal, intermediate, and ventral. The dorsal hippocampus, which corresponds to the posterior hippocampus in primates, performs primarily cognitive functions. The ventral (anterior in primates) relates to stress, emotion, and affect. Strikingly, gene expression in the dorsal hippocampus correlates with cortical regions involved in information processing, while genes expressed in the ventral hippocampus correlate with regions involved in emotion and stress (amygdala and hypothalamus).
• Cortical Maps and White Matter Tracts following Long Period of Visual Deprivation and Retinal Image Restoration
  - Neuron 65(1):21-31 (2010)
  Abnormal visual input during development has dramatic effects on the visual system. How does the adult visual system respond when input is corrected? MM lost his left eye and became blind in the right due to corneal damage at the age of 3. At age 46, MM regained his retinal image, but his visual abilities, even seven years following the surgery, remain severely limited, and he does not rely on vision for daily life. Neuroimaging measurements reveal several differences among MM, sighted controls, sighted monocular, and early blind subjects. We speculate that these differences stem from damage during the critical period in development of retinal neurons with small, foveal receptive fields. In this case, restoration of functional vision requires more than improving retinal image contrast. In general, visual restoration will require accounting for the developmental trajectory of the individual and the consequences of the early deprivation on cortical circuitry.
• Genetically Increased Cell-Intrinsic Excitability Enhances Neuronal Integration into Adult Brain Circuits
  - Neuron 65(1):32-39 (2010)
  New neurons are added to the adult brain throughout life, but only half ultimately integrate into existing circuits. Sensory experience is an important regulator of the selection of new neurons but it remains unknown whether experience provides specific patterns of synaptic input or simply a minimum level of overall membrane depolarization critical for integration. To investigate this issue, we genetically modified intrinsic electrical properties of adult-generated neurons in the mammalian olfactory bulb. First, we observed that suppressing levels of cell-intrinsic neuronal activity via expression of ESKir2.1 potassium channels decreases, whereas enhancing activity via expression of NaChBac sodium channels increases survival of new neurons. Neither of these modulations affects synaptic formation. Furthermore, even when neurons are induced to fire dramatically altered patterns of action potentials, increased levels of cell-intrinsic activity completely blocks cell death! triggered by NMDA receptor deletion. These findings demonstrate that overall levels of cell-intrinsic activity govern survival of new neurons and precise firing patterns are not essential for neuronal integration into existing brain circuits.
• 5-HT1A Autoreceptor Levels Determine Vulnerability to Stress and Response to Antidepressants
  - Neuron 65(1):40-52 (2010)
  Most depressed patients don't respond to their first drug treatment, and the reasons for this treatment resistance remain enigmatic. Human studies implicate a polymorphism in the promoter of the serotonin-1A (5-HT1A) receptor gene in increased susceptibility to depression and decreased treatment response. Here we develop a new strategy to manipulate 5-HT1A autoreceptors in raphe nuclei without affecting 5-HT1A heteroreceptors, generating mice with higher (1A-High) or lower (1A-Low) autoreceptor levels. We show that this robustly affects raphe firing rates, but has no effect on either basal forebrain serotonin levels or conflict-anxiety measures. However, compared to 1A-Low mice, 1A-High mice show a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to antidepressant, modeling patients with the 5-HT1A risk allele. Furthermore, reducing 5-HT1A autoreceptor levels prior to antidepressant treatment is sufficient to conv! ert nonresponders into responders. These results establish a causal relationship between 5-HT1A autoreceptor levels, resilience under stress, and response to antidepressants.
• Delivery of GABAARs to Synapses Is Mediated by HAP1-KIF5 and Disrupted by Mutant Huntingtin
  - Neuron 65(1):53-65 (2010)
  The density of GABAA receptors (GABAARs) at synapses regulates brain excitability, and altered inhibition may contribute to Huntington's disease, which is caused by a polyglutamine repeat in the protein huntingtin. However, the machinery that delivers GABAARs to synapses is unknown. We demonstrate that GABAARs are trafficked to synapses by the kinesin family motor protein 5 (KIF5). We identify the adaptor linking the receptors to KIF5 as the huntingtin-associated protein 1 (HAP1). Disrupting the HAP1-KIF5 complex decreases synaptic GABAAR number and reduces the amplitude of inhibitory postsynaptic currents. When huntingtin is mutated, as in Huntington's disease, GABAAR transport and inhibitory synaptic currents are reduced. Thus, HAP1-KIF5-dependent GABAAR trafficking is a fundamental mechanism controlling the strength of synaptic inhibition in the brain. Its disruption by mutant huntingtin may explain some of the defects in brain information processing occurring in Hu! ntington's disease and provides a molecular target for therapeutic approaches.
• Increased Expression of α-Synuclein Reduces Neurotransmitter Release by Inhibiting Synaptic Vesicle Reclustering after Endocytosis
  - Neuron 65(1):66-79 (2010)
  The protein α-synuclein accumulates in the brain of patients with sporadic Parkinson's disease (PD), and increased gene dosage causes a severe, dominantly inherited form of PD, but we know little about the effects of synuclein that precede degeneration. α-Synuclein localizes to the nerve terminal, but the knockout has little if any effect on synaptic transmission. In contrast, we now find that the modest overexpression of α-synuclein, in the range predicted for gene multiplication and in the absence of overt toxicity, markedly inhibits neurotransmitter release. The mechanism, elucidated by direct imaging of the synaptic vesicle cycle, involves a specific reduction in size of the synaptic vesicle recycling pool. Ultrastructural analysis demonstrates reduced synaptic vesicle density at the active zone, and imaging further reveals a defect in the reclustering of synaptic vesicles after endocytosis. Increased levels of α-synuclein thus produce a specific, physiological! defect in synaptic vesicle recycling that precedes detectable neuropathology.
• SynDIG1: An Activity-Regulated, AMPA- Receptor-Interacting Transmembrane Protein that Regulates Excitatory Synapse Development
  - Neuron 65(1):80-93 (2010)
  During development of the central nervous system, precise synaptic connections between presynaptic and postsynaptic neurons are formed. While significant progress has been made in our understanding of AMPA receptor trafficking during synaptic plasticity, less is known about the molecules that recruit AMPA receptors to nascent synapses during synaptogenesis. Here we identify a type II transmembrane protein (SynDIG1) that regulates AMPA receptor content at developing synapses in dissociated rat hippocampal neurons. SynDIG1 colocalizes with AMPA receptors at synapses and at extrasynaptic sites and associates with AMPA receptors in heterologous cells and brain. Altered levels of SynDIG1 in cultured neurons result in striking changes in excitatory synapse number and function. SynDIG1-mediated synapse development is dependent on association with AMPA receptors via its extracellular C terminus. Intriguingly, SynDIG1 content in dendritic spines is regulated by neuronal activit! y. Altogether, we define SynDIG1 as an activity-regulated transmembrane protein that regulates excitatory synapse development.
• Dual Roles for Perivascular Macrophages in Immune-to-Brain Signaling
  - Neuron 65(1):94-106 (2010)
  Cytokines produced during infection/inflammation activate adaptive central nervous system (CNS) responses, including acute stress responses mediated by the hypothalamo-pituitary-adrenal (HPA) axis. The mechanisms by which cytokines engage HPA control circuitry remain unclear, though stimulated release of prostanoids from neighboring vascular cells has been implicated in this regard. How specific vascular cell types, endothelial cells (ECs) versus perivascular cells (PVCs; a subset of brain-resident macrophages), participate in this response remains unsettled. We exploited the phagocytic activity of PVCs to deplete them in rats by central injection of a liposome-encapsulated proapoptotic drug. This manipulation abrogated CNS and hormonal indices of HPA activation under immune challenge conditions (interleukin-1) that activated prostanoid synthesis only in PVCs, while enhancing these responses to stimuli (lipopolysaccharide) that engaged prostanoid production by ECs as w! ell. Thus, PVCs provide both prostanoid-mediated drive to the HPA axis and an anti-inflammatory action that constrains endothelial and overall CNS responses to inflammatory insults.
• Synaptic and Network Mechanisms of Sparse and Reliable Visual Cortical Activity during Nonclassical Receptive Field Stimulation
  - Neuron 65(1):107-121 (2010)
  During natural vision, the entire visual field is stimulated by images rich in spatiotemporal structure. Although many visual system studies restrict stimuli to the classical receptive field (CRF), it is known that costimulation of the CRF and the surrounding nonclassical receptive field (nCRF) increases neuronal response sparseness. The cellular and network mechanisms underlying increased response sparseness remain largely unexplored. Here we show that combined CRF + nCRF stimulation increases the sparseness, reliability, and precision of spiking and membrane potential responses in classical regular spiking (RSC) pyramidal neurons of cat primary visual cortex. Conversely, fast-spiking interneurons exhibit increased activity and decreased selectivity during CRF + nCRF stimulation. The increased sparseness and reliability of RSC neuron spiking is associated with increased inhibitory barrages and narrower visually evoked synaptic potentials. Our experimental observations! were replicated with a simple computational model, suggesting that network interactions among neuronal subtypes ultimately sharpen recurrent excitation, producing specific and reliable visual responses.
• Manipulation of a Central Auditory Representation Shapes Learned Vocal Output
  - Neuron 65(1):122-134 (2010)
  Learned vocalizations depend on the ear's ability to monitor and ultimately instruct the voice. Where is auditory feedback processed in the brain, and how does it modify motor networks for learned vocalizations? Here we addressed these questions using singing-triggered microstimulation and chronic recording methods in the singing zebra finch, a small songbird that relies on auditory feedback to learn and maintain its species-typical vocalizations. Manipulating the singing-related activity of feedback-sensitive thalamic neurons subsequently triggered vocal plasticity, constraining the central pathway and functional mechanisms through which feedback-related information shapes vocalization. PaperFlick 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 (25180 K)
• Mechanisms Underlying Dopamine-Mediated Reward Bias in Compulsive Behaviors
  - Neuron 65(1):135-142 (2010)
  Pathological behaviors such as problem gambling or shopping are characterized by compulsive choice despite alternative options and negative costs. Reinforcement learning algorithms allow a computation of prediction error, a comparison of actual and expected outcomes, which updates our predictions and influences our subsequent choices. Using a reinforcement learning model, we show data consistent with the idea that dopamine agonists in susceptible individuals with Parkinson's disease increase the rate of learning from gain outcomes. Dopamine agonists also increase striatal prediction error activity, thus signifying a "better than expected" outcome. Thus, our findings are consistent with a model whereby a distorted estimation of the gain cue underpins a choice bias toward gains.