Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Neurons and Synapses -- Recent Research


Nature 459, 703-707 (4 June 2009)

Mechanism of differential control of NMDA receptor activity by NR2 subunits

Marc Gielen, Beth Siegler Retchless, Laetitia Mony, Jon W. Johnson & Pierre Paoletti

Laboratoire de Neurobiologie, École Normale Supérieure, CNRS, 46 rue d'Ulm, 75005 Paris, France

Department of Neuroscience, University of Pittsburgh, A210 Langely Hall, Pittsburgh, Pennsylvania 15260, USA

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are a major class of excitatory neurotransmitter receptors in the central nervous system. They form glutamate-gated ion channels that are highly permeable to calcium and mediate activity-dependent synaptic plasticity. NMDAR dysfunction is implicated in multiple brain disorders, including stroke, chronic pain and schizophrenia. NMDARs exist as multiple subtypes with distinct pharmacological and biophysical properties that are largely determined by the type of NR2 subunit (NR2A to NR2D) incorporated in the heteromeric NR1/NR2 complex. A fundamental difference between NMDAR subtypes is their channel maximal open probability (Po), which spans a 50-fold range from about 0.5 for NR2A-containing receptors to about 0.01 for receptors containing NR2C and NR2D; NR2B-containing receptors have an intermediate value (about 0.1). These differences in Po confer unique charge transfer capacities and signalling properties on each receptor subtype. The molecular basis for this profound difference in activity between NMDAR subtypes is unknown. Here we show that the subunit-specific gating of NMDARs is controlled by the region formed by the NR2 amino-terminal domain (NTD), an extracellular clamshell-like domain previously shown to bind allosteric inhibitors, and the short linker connecting the NTD to the agonist-binding domain (ABD). The subtype specificity of NMDAR Po largely reflects differences in the spontaneous (ligand-independent) equilibrium between open-cleft and closed-cleft conformations of the NR2-NTD. This NTD-driven gating control also affects pharmacological properties by setting the sensitivity to the endogenous inhibitors zinc and protons. Our results provide a proof of concept for a drug-based bidirectional control of NMDAR activity by using molecules acting either as NR2-NTD 'closers' or 'openers' promoting receptor inhibition or potentiation, respectively.


Science 6 March 2009: Vol. 323. no. 5919, pp. 1313 - 1319

Functional Proteomics Identify Cornichon Proteins as Auxiliary Subunits of AMPA Receptors

Jochen Schwenk,1 Nadine Harmel,1 Gerd Zolles,1 Wolfgang Bildl,1 Akos Kulik,4 Bernd Heimrich,4 Osamu Chisaka,6 Peter Jonas,3 Uwe Schulte,1,2 Bernd Fakler,1,5 Nikolaj Klöcker1

1 Institute of Physiology II, University of Freiburg, Engesserstrasse 4, 79108 Freiburg, Germany.
2 Logopharm GmbH, Engesserstrasse 4, 79108 Freiburg, Germany.
3 Institute of Physiology I, University of Freiburg, Engesserstrasse 4, 79108 Freiburg, Germany.
4 Institute of Anatomy and Cell Biology, University of Freiburg, Albertstrasse 23, 79104 Freiburg, Germany.
5 Center for Biological Signaling Studies (bioss), Albertstrasse 10, 79104 Freiburg, Germany.
6 Department of Cell and Developmental Biology, Kyoto University, Kyoto 606-8502, Japan.

Glutamate receptors of the AMPA-subtype (AMPARs), together with the transmembrane AMPAR regulatory proteins (TARPs), mediate fast excitatory synaptic transmission in the mammalian brain.

Fast excitatory synaptic transmission in the mammalian CNS is mostly mediated by AMPA receptors (AMPARs), ligand-gated ion channels that are activated by glutamate released from the presynaptic terminals. On activation, AMPARs provide the transient excitatory postsynaptic current (EPSC) that depolarizes the membrane and initiates downstream processes, such as the generation of action potentials or synaptic plasticity. The time course and amplitude of AMPAR-mediated EPSCs exhibit considerable variability among neurons and synapses and strongly depend on the properties of the postsynaptic AMPARs.

AMPARs are tetrameric assemblies of {alpha}subunits with distinct properties that are encoded by the glutamate receptor (GluR) genes GluR-A to GluR-D and their variations resulting from alternative splicing and RNA editing. In most central neurons, multiple variants of these GluR proteins are expressed and assembled into heteromultimeric channels that display a wide range of gating kinetics and Ca2+ permeabilities. In addition to the {alpha}subunits, the properties of the AMPARs are modulated by a family of transmembrane AMPAR regulatory proteins (TARPs). The TARPs coassemble with the GluR proteins and through direct protein-protein interactions affect the gating, permeability and pharmacology of the AMPARs. Furthermore, the TARPs influence the number and subcellular localization of AMPARs by promoting their trafficking to the plasma membrane and their targeting to the synapse.

The results on channel kinetics indicated that the CNIH proteins extensively modify the gating properties of AMPARs, probably by stabilizing the open state of the receptor channels; this stabilizing effect promotes slowing of deactivation and desensitization, without major effects on channel activation or recovery from desensitization.


Nature 459, 93-97 (7 May 2009)

Compound vesicle fusion increases quantal size and potentiates synaptic transmission

Liming He1,3, Lei Xue1,3, Jianhua Xu1, Benjamin D. McNeil1, Li Bai1, Ernestina Melicoff2, Roberto Adachi2 & Ling-Gang Wu1

National Institute of Neurological Disorders and Stroke, 35 Convent Drive, Building 35, Room 2B-1012, Bethesda, Maryland 20892, USA

Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, 2121 West Holcombe Boulevard, Box 1100, Houston, Texas 77030, USA.

Exocytosis at synapses involves fusion between vesicles and the plasma membrane. Here we report the existence of compound fusion, its underlying mechanism, and its role at a nerve terminal containing conventional active zones in rats and mice. These results suggest a new route of exocytosis and endocytosis composed of three steps. First, calcium/synaptotagmin mediates compound fusion between vesicles. Second, exocytosis of compound vesicles increases quantal size, which increases synaptic strength and contributes to the generation of post-tetanic potentiation. Third, exocytosed compound vesicles are retrieved via bulk endocytosis. We suggest that this vesicle cycling route be included in models of synapses.