A role for cGMP-dependent protein kinase II in AMPA receptor trafficking and synaptic plasticity

Background: Trafficking of AMPA receptors (AMPARs) underlies the activity-dependent modification of synaptic strength and is regulated by specific interactions of AMPAR subunits with other proteins. We have reported (Serulle et al., 2007) 1 that the AMPAR subunit GluR1 binds the cGMP-dependent kinase type II (cGKII) adjacent to the kinase catalytic site, and that this interaction is increased by cGMP. In this complex, cGKII phosphorylates GluR1 at serine 845 (S845) leading to an increase of GluR1 on the plasma membrane. In neurons, cGMP is produced by soluble guanylate cyclase (sGC), which is activated by nitric oxide (NO), which is produced by nNOS under the control of the NMDA receptor. Results: To distinguish the mechanism, we have measured the rate of exogenous GluR1 endocytosis in cultured primary neurons, either the wild type or the S845A or S845D mutants (Figure 1). We find that the S845A mutant (which cannot be phosphorylated) is endocytosed at rate of the wild type, while S845D (phosphomimetic) is endocytosed at a lower rate. Also, cGMP treatment, which elevates the endogenous GluR1 plasma membrane levels (Figure 2A), reduced the rate of of GluR1 endocytosis (Figure 2B). Figure 1 Endocytosis of HAGluR1 is time dependent and is inhibited by the phosphomimetic mutation, S845D Endocytosis of HAGluR1 is time dependent and is inhibited by the phosphomimetic mutation, S845D. Figure 2 Elevation of surface GluR1 and reduction of GluR1 endocytosis by cGMP Elevation of surface GluR1 and reduction of GluR1 endocytosis by cGMP. A. cGMP, elevates surface GluR1. B. cGMP decreases endocytosis of GluR1. Conclusion: These data suggest that S845 phosphorylation increases the plasma membrane levels of GluR1 by reducing the rate of endocytosis

Differential effects of natural rewards and pain on vesicular glutamate transporter expression in the nucleus accumbens

Background: Pain and natural rewards such as food elicit different behavioral effects. Both pain and rewards, however, have been shown to alter synaptic activities in the nucleus accumbens (NAc), a key component of the brain reward system. Mechanisms by which external stimuli regulate plasticity at NAc synapses are largely unexplored. Medium spiny neurons (MSNs) from the NAc receive excitatory glutamatergic inputs and modulatory dopaminergic and cholinergic inputs from a variety of cortical and subcortical structures. Glutamate inputs to the NAc arise primarily from prefrontal cortex, thalamus, amygdala, and hippocampus, and different glutamate projections provide distinct synaptic and ultimately behavioral functions. The family of vesicular glutamate transporters (VGLUTs 1–3) plays a key role in the uploading of glutamate into synaptic vesicles. VGLUT1-3 isoforms have distinct expression patterns in the brain, but the effects of external stimuli on their expression patterns have not been studied. Results: In this study, we use a sucrose self-administration paradigm for natural rewards, and spared nerve injury (SNI) model for chronic pain. We examine the levels of VGLUTs (1–3) in synaptoneurosomes of the NAc in these two behavioral models. We find that chronic pain leads to a decrease of VGLUT1, likely reflecting decreased projections from the cortex. Pain also decreases VGLUT3 levels, likely representing a decrease in projections from GABAergic, serotonergic, and/or cholinergic interneurons. In contrast, chronic consumption of sucrose increases VGLUT3 in the NAc, possibly reflecting an increase from these interneuron projections. Conclusion: Our study shows that natural rewards and pain have distinct effects on the VGLUT expression pattern in the NAc, indicating that glutamate inputs to the NAc are differentially modulated by rewards and pain

For the Progress of “Faustus and Helen”: Crane, Whitman, and the Metropolitan Progress Poem

This essay is meant to invigorate a critical discussion of the progress poem—a genre that, while prevalent in American literature, has been virtually ignored by critics and scholars. In lieu of tackling the genre in its entirety, a project too large for just one article, the author focuses the argument through the well-known alignment between Walt Whitman and Hart Crane on the subject of the modern city. It is through the progress poem genre that Crane and Whitman’s peculiar place in metropolitan poetics can best be understood, and it is through their poetry that scholars can begin to approach the broader issue of the progress poem’s place in American literature. Cet article vise à soulever un débat critique au sujet de la poésie du progrès, un genre courant dans la littérature étatsunienne, mais pratiquement ignoré par les critiques et les commentateurs. Plutôt que d’aborder le genre dans son entièreté – un projet qui déborde du cadre d’un article –, l’auteur resserre l’argumentation autour du parallèle bien connu entre Walt Whitman et Hart Crane concernant le traitement de la ville moderne. C’est la poésie du progrès en tant que genre qui permet le mieux de comprendre la place particulière qu’occupent ces deux auteurs dans la poésie métropolitaine, et c’est par leurs poèmes que les chercheurs peuvent aborder la question plus vaste de la place du poème sur le progrès dans la littérature étatsunienne

Ephrin-A5 and EphA5 Interaction Induces Synaptogenesis during Early Hippocampal Development

Synaptogenesis is a fundamental step in neuronal development. For spiny glutamatergic synapses in hippocampus and cortex, synaptogenesis involves adhesion of pre and postsynaptic membranes, delivery and anchorage of pre and postsynaptic structures including scaffolds such as PSD-95 and NMDA and AMPA receptors, which are glutamate-gated ion channels, as well as the morphological maturation of spines. Although electrical activity-dependent mechanisms are established regulators of these processes, the mechanisms that function during early development, prior to the onset of electrical activity, are unclear. The Eph receptors and ephrins provide cell contact-dependent pathways that regulate axonal and dendritic development. Members of the ephrin-A family are glycosyl-phosphatidylinositol-anchored to the cell surface and activate EphA receptors, which are receptor tyrosine kinases.Here we show that ephrin-A5 interaction with the EphA5 receptor following neuron-neuron contact during early development of hippocampus induces a complex program of synaptogenic events, including expression of functional synaptic NMDA receptor-PSD-95 complexes plus morphological spine maturation and the emergence of electrical activity. The program depends upon voltage-sensitive calcium channel Ca2+ fluxes that activate PKA, CaMKII and PI3 kinase, leading to CREB phosphorylation and a synaptogenic program of gene expression. AMPA receptor subunits, their scaffolds and electrical activity are not induced. Strikingly, in contrast to wild type, stimulation of hippocampal slices from P6 EphA5 receptor functional knockout mice yielded no NMDA receptor currents.These studies suggest that ephrin-A5 and EphA5 signals play a necessary, activity-independent role in the initiation of the early phases of synaptogenesis. The coordinated expression of the NMDAR and PSD-95 induced by eprhin-A5 interaction with EphA5 receptors may be the developmental switch that induces expression of AMPAR and their interacting proteins and the transition to activity-dependent synaptic regulation

Calcineurin Mediates Synaptic Scaling Via Synaptic Trafficking of Ca²⁺-Permeable AMPA Receptors

<div><p>Homeostatic synaptic plasticity is a negative-feedback mechanism for compensating excessive excitation or inhibition of neuronal activity. When neuronal activity is chronically suppressed, neurons increase synaptic strength across all affected synapses via synaptic scaling. One mechanism for this change is alteration of synaptic AMPA receptor (AMPAR) accumulation. Although decreased intracellular Ca²⁺ levels caused by chronic inhibition of neuronal activity are believed to be an important trigger of synaptic scaling, the mechanism of Ca²⁺-mediated AMPAR-dependent synaptic scaling is not yet understood. Here, we use dissociated mouse cortical neurons and employ Ca²⁺ imaging, electrophysiological, cell biological, and biochemical approaches to describe a novel mechanism in which homeostasis of Ca²⁺ signaling modulates activity deprivation-induced synaptic scaling by three steps: (1) suppression of neuronal activity decreases somatic Ca²⁺ signals; (2) reduced activity of calcineurin, a Ca²⁺-dependent serine/threonine phosphatase, increases synaptic expression of Ca²⁺-permeable AMPARs (CPARs) by stabilizing GluA1 phosphorylation; and (3) Ca²⁺ influx via CPARs restores CREB phosphorylation as a homeostatic response by Ca²⁺-induced Ca²⁺ release from the ER. Therefore, we suggest that synaptic scaling not only maintains neuronal stability by increasing postsynaptic strength but also maintains nuclear Ca²⁺ signaling by synaptic expression of CPARs and ER Ca²⁺ propagation.</p></div