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Urs Gerber

Publications and source records attributed to Urs Gerber.

14 recordsLinked to original sources
PubMed2006

Metabotropic glutamate receptors: intracellular signaling pathways.

Metabotropic glutamate receptors are classified into three groups, primarily on the basis of sequence similarity and whether they positively couple to the phospholipase C cascade or negatively couple to adenylyl cyclases. The past decade of research, drawing on sophisticated molecular approaches, has revealed a multitude of additional intracellular components that assemble as protein scaffolds around neuronal metabotropic glutamate receptors, establishing functional links to postsynaptic density structures, to membrane-bound enzymes and ion channels, and to the nucleus. Characterization of these novel transduction mechanisms is providing new insights into the roles of metabotropic glutamate receptors in the regulation and modulation of diverse functions in the nervous system.

Animals↗
PubMed2006

NMDA receptors and the differential ischemic vulnerability of hippocampal neurons.

Transient cerebral ischemia causes an inhomogeneous pattern of cell death in the brain. We investigated mechanisms, which may underlie the greater susceptibility of hippocampal CA1 vs. CA3 pyramidal cells to ischemic insult. Using an in vitro oxygen-glucose deprivation (OGD) model of ischemia, we found that N-methyl-D-aspartate (NMDA) responses were enhanced in the more susceptible CA1 pyramidal cells and transiently depressed in the resistant CA3 pyramidal cells. The long-lasting potentiation of NMDA responses in CA1 cells was associated with delayed cell death and was prevented by blocking tyrosine kinase-dependent up-regulation of NMDA receptor function. In CA3 cells, the energy deprivation-induced transient depression of NMDA responses was converted to potentiation by blocking protein phosphatase signalling. These results suggest that energy deprivation differentially shifts the intracellular equilibrium between the tyrosine kinase and phosphatase activities that modulate NMDA responses in CA1 and CA3 pyramidal cells. Therapeutic modulation of tyrosine phosphorylation may thus prove beneficial in mitigating ischemia-induced neuronal death in vulnerable brain areas.

Animals↗
PubMed2005

Muscarinic receptor stimulation reduces NMDA responses in CA3 hippocampal pyramidal cells via Ca2+-dependent activation of tyrosine phosphatase.

N-methyl-D-aspartate (NMDA)-type glutamate receptors perform critical functions during the development of the nervous system and in the initiation of synaptic plasticity. An important mechanism in setting the gain of NMDA receptors involves the stimulation of G-protein-coupled receptors (GPCRs), which through activation of protein tyrosine kinases leads to an upregulation of NMDA receptors. In contrast, little is known about how NMDA receptors are downregulated. In the present study, we characterized a signaling pathway that mediates the depression of NMDA receptor function in response to stimulation of muscarinic acetylcholine receptors. Whole-cell patch-clamp recordings obtained from CA3 pyramidal cells in organotypic slice cultures revealed that under conditions of low intracellular calcium buffering application of muscarine-depressed NMDA receptor current. The sensitivity of this response to pirenzipine indicated that the M1 acetylcholine receptor is mediating this depression. The muscarine-induced depression of NMDA current was prevented by blocking G-protein function or after depleting intracellular Ca2+ stores with cyclopiazonic acid. Inhibitors of calmodulin prevented the depression whereas blocking calcineurin enhanced the depression of NMDA currents. Blocking tyrosine phosphatase activity with pervanandate converted the muscarine-induced depression into a potentiation of NMDA currents, whereas blocking protein kinase A (H-89), Src kinase (PP2, SU6656), or PKC (GF 109203X) failed to prevent the depression of NMDA currents. As Src tyrosine kinase is known to phosphorylate and upregulate NMDA receptors, we propose that a protein tyrosine phosphatase(s) counteracting the action of Src is the final target in the mAChR-dependent inhibitory signaling cascade. Our data are consistent with a transduction cascade comprising an M1 acetylcholine receptor-->G-protein-->Ca2+ release-->calmodulin-->tyrosine phosphatase.

Animals↗
PubMed2004

A frequency-dependent switch from inhibition to excitation in a hippocampal unitary circuit.

The hippocampus, a brain structure essential for memory and cognition, is classically represented as a trisynaptic excitatory circuit. Recent findings challenge this view, particularly with regard to the mossy fibre input to CA3, the second synapse in the trisynaptic pathway. Thus, the powerful mossy fibre input to CA3 pyramidal cells might mediate both synaptic excitation and inhibition. Here we show, by recording from connected cell pairs in rat entorhinal-hippocampal slice cultures, that single action potentials in a dentate granule cell evoke a net inhibitory signal in a pyramidal cell. The hyperpolarization is due to disynaptic feedforward inhibition, which overwhelms monosynaptic excitation. Interestingly, this net inhibitory synaptic response changes to an excitatory signal when the frequency of presynaptic action potentials increases. The process responsible for this switch involves the facilitation of monosynaptic excitatory transmission coupled with rapid depression of inhibitory circuits. This ability to immediately switch the polarity of synaptic responses constitutes a novel synaptic mechanism, which might be crucial to the state-dependent processing of information in associative hippocampal networks.

Action Potentials↗
PubMed2004

Differential calcium-dependent modulation of NMDA currents in CA1 and CA3 hippocampal pyramidal cells.

Neuronal Ca2+ influx via NMDA receptors (NMDARs) is essential for the development and plasticity of synapses but also triggers excitotoxic cell death when critical intracellular levels are exceeded. Therefore, finely equilibrated mechanisms are necessary to ensure that NMDAR function is maintained within a homeostatic range. Here we describe a pronounced difference in the modulation of NMDA currents in two closely related hippocampal cell types, the CA1 and the CA3 pyramidal cells (PCs). Manipulations that increase intracellular Ca2+ levels strongly depressed NMDA currents in CA3 with only minor effects in CA1 PCs. Furthermore, activation of G(q)-coupled metabotropic receptors potentiated NMDA currents in CA1 PCs but depressed them in CA3 PCs. Interestingly, the CA3 type modulation of NMDARs could be converted into CA1-like behavior, and vice versa, by increasing Ca2+ buffering in CA3 cells or decreasing Ca2+ buffering in CA1 cells, respectively. Our data suggest that a differential Ca2+ sensitivity of the regulatory cascades targeting NMDARs plays a key role in determining the direction and magnitude of NMDA responses in various types of neurons. These findings may have important implications for NMDA receptor-dependent synaptic plasticity and the differential sensitivity of CA1 and CA3 PCs to NMDAR-dependent ischemic cell death.

Animals↗
PubMed2003

Group I metabotropic glutamate receptors activate a calcium-sensitive transient receptor potential-like conductance in rat hippocampus.

In CA3 pyramidal neurons from organotypic slice cultures, activation of G(q)-coupled group I metabotropic glutamate receptors (mGluRs) induces a non-selective cationic conductance that enhances excitability. We have found that this response shares several properties with conductances that are mediated by the transient receptor potential (TRP) family of ion channels, including inhibition by La(3+), 2-aminoethoxydiphenylborane (2APB), cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12,330A) and a doubly rectifying current-voltage relationship. Stimulation of mGluR1 and mGluR5 converged to activate the TRP-like conductance in a synergistic manner, and activation of either subtype alone produced only a fraction of the normal response. Activation of the cationic current required elevated intracellular Ca(2+). Chelating intracellular Ca(2+) or blocking Ca(2+) entry through voltage-gated Ca(2+) channels attenuated responses to the activation of mGluRs. Conversely, raising intracellular Ca(2+) potentiated mGluR activation of the TRP-like conductance. Under control conditions, blocking G protein activation using intracellular GDPbetaS with or without N-(2, 6-dimethylphenylcarbamoylmethyl) triethylammonium chloride (QX-314) prevented mGluR-mediated activation of the TRP-like conductance. Following G protein blockade, however, the coupling between mGluRs 1 and/or 5 and the TRP-like conductance was rescued by increasing intracellular Ca(2+). This suggests that a G protein-independent signalling pathway is also activated by group I mGluRs. Such a pathway may represent an alternative transduction mechanism to maintain metabotropic responses under conditions where G proteins are functionally uncoupled from their cognate receptors.

Animals↗
PubMed2003

Metabotropic glutamate receptors in vertebrate retina.

A striking feature in visual information processing is the fact that the primary signaling elements, the rods and the cones, are hyperpolarized and thus inhibited by light, the physiological stimulus. Light effectively shuts down neurotransmitter release by the photoreceptors onto the second-order retinal neurons. It has long been recognized that a sign-inverting synapse utilizing a specialized receptor is required to translate the inhibitory photoreceptor response into an excitatory signal suitable for transmission to the visual cortex. Although the first clues to the underlying mechanism were discovered in the 1970s, the actual receptor initiating the sign inversion in the ON bipolar cells was only identified in 1993. This receptor was found to belong to the family of metabotropic glutamate receptors (mGluRs) and is referred to as mGluR6. Subsequent studies have focused on the intracellular transduction pathway allowing mGluR6 to mediate a hyperpolarizing response to the neurotransmitter glutamate. The mGluR family of receptors comprises seven additional members, all of which are also found in retinal cells. Their function is to modulate rather than to transmit visual signals. In this brief overview, I describe the basic properties of mGluRs and summarize their roles in retinal signaling.

Animals↗
PubMed2003

Homer-1a/Vesl-1S enhances hippocampal synaptic transmission.

Homer/Vesl proteins are involved in regulating metabotropic glutamate receptors, synaptogenesis, dendritic spine development and axonal pathfinding. We investigated the potential modulation of glutamatergic synaptic transmission by the immediate early gene product Homer-1a/Vesl-1S and by the constitutively expressed long-form Homer-1c/Vesl-1L in CA1 pyramidal cells from cultured rat hippocampal slices. Semliki Forest virus vector-mediated overexpression of Homer-1a enhanced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function, but did not detectably affect N-methyl-d-aspartate (NMDA) receptor function and presynaptic glutamate release. Overexpression of Homer-1c, by contrast, did not alter synaptic transmission. To corroborate our electrophysiological results obtained in slice cultures, we performed quantitative immunocytochemistry in cultures of dissociated hippocampal neurons. Homer-1a also increased synaptic clustering of AMPA but not NMDA receptors, whereas Homer-1c had no detectable effect. Our results show that Homer-1a potentiates synaptic AMPA receptor function, supporting a critical role for Homer-1a in hippocampal synaptic plasticity.

Animals↗
PubMed2002

Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes.

Molecular processes regulating the gain of NMDA receptors modulate diverse physiological and pathological responses in the CNS. Group I metabotropic glutamate receptors (mGluRs), which neighbor NMDA receptors and which can be coactivated by synaptically released glutamate, couple to several different second messenger pathways, each of which could target NMDA receptors. In CA3 pyramidal cells we show that the activation of mGluR1 potentiates NMDA current via a G-protein-independent mechanism involving Src kinase activation. In contrast, mGluR5-mediated enhancement of NMDA current requires G-protein activation, triggering a signaling cascade including protein kinase C and Src. These results indicate that one neurotransmitter, glutamate, can activate two distinct and independent signaling systems to target the same effector. These two pathways are likely to contribute significantly to the highly differentiated control of NMDA receptor function.

Animals↗
PubMed2002

Slow feedback inhibition in the CA3 area of the rat hippocampus by synergistic synaptic activation of mGluR1 and mGluR5.

Interneurons are critical in regulating the excitability of principal cells in neuronal circuits, thereby modulating the output of neuronal networks. We investigated synaptically evoked inhibitory responses in CA3 pyramidal cells mediated by metabotropic glutamate receptors (mGluRs) expressed somatodendritically by interneurons. Although pharmacological activation of mGluRs in interneurons has been shown to enhance their excitability, the inability to record mGluR-mediated synaptic responses has precluded detailed characterization of mGluR function in hippocampal interneurons. We found that a single extracellular pulse in CA3 stratum pyramidale was sufficient to induce disynaptic inhibitory responses mediated by postsynaptic mGluRs of the interneurons in CA3 pyramidal cells of hippocampal slice cultures. The disynaptic inhibitory response followed a short-latency monosynaptic inhibitory response, and was observed at stimulus intensities evoking half-maximal monosynaptic IPSCs. Synergistic activation of mGluR1 and mGluR5 was required to induce the full inhibitory response. When recordings were obtained from interneurons in CA3 stratum radiatum or stratum oriens, a single extracellular stimulus induced a slow inward cationic current with a time course corresponding to the slow inhibitory response measured in pyramidal cells. DCG IV, a group II mGluR agonist, which specifically blocks synaptic transmission through mossy fibres, had no effect on mGluR-mediated synaptic responses in interneurons, suggesting that feed-forward inhibition via mossy fibres is not involved. Thus, postsynaptic mGluR1 and mGluR5 in hippocampal interneurons cooperatively mediate slow feedback inhibition of CA3 pyramidal cells. This mechanism may allow interneurons to monitor activity levels from populations of neighbouring principal cells to adapt inhibitory tone to the state of the network.

Animals↗
PubMed2002

Beta-alanine and taurine as endogenous agonists at glycine receptors in rat hippocampus in vitro.

Electrophysiological and pharmacological properties of glycine receptors were characterized in hippocampal organotypic slice cultures. In the presence of ionotropic glutamate and GABA(B) receptor antagonists, pressure-application of glycine onto CA3 pyramidal cells induced a current associated with increased chloride conductance, which was inhibited by strychnine. Similar chloride currents could also be induced with beta-alanine or taurine. Whole-cell glycine responses were significantly greater in CA3 pyramidal cells than in CA1 pyramidal cells and dentate granule cells, while responses to GABA were similar among these three cell types. Although these results demonstrate the presence of functional glycine receptors in the hippocampus, no evidence for their activation during synaptic stimulation was found. Gabazine, a selective GABA(A) receptor antagonist, totally blocked evoked IPSCs in CA3 pyramidal cells. Glycine receptor activation is not dependent on transporter-controlled levels of extracellular glycine, as no chloride current was observed in response to sarcosine, an inhibitor of glycine transporters. In contrast, application of guanidinoethanesulfonic acid, an uptake inhibitor of beta-alanine and taurine, induced strychnine-sensitive chloride current in the presence of gabazine. These data indicate that modulation of transporters for the endogenous amino acids, beta-alanine and taurine, can regulate tonic activation of glycine receptors, which may function in maintenance of inhibitory tone in the hippocampus.

Animals↗
PubMed1992

Characterization of l-2-Amino-4-Phosphonobutanoate Action Following Sensitization by Quisqualate in Rat Hippocampal Slice Cultures.

An excitatory action of l-2-amino-4-phosphonobutanoate (l-AP4), a glutamate analogue, is observed following pre-exposure of tissue to quisqualate. We have studied the mechanism of sensitization of l-AP4 responses by quisqualate in voltage-clamped CA3 pyramidal cells in rat hippocampal slice cultures in the presence of tetrodotoxin. Prior to quisqualate addition, CA3 cells did not respond to l-AP4 (50 - 1000 microM). Following brief application of quisqualate (500 nM for 30 s), l-AP4 (50 - 200 microM) induced a complex excitatory response which could be obtained for >1 h. l-AP4 caused an ionotropic inward current associated with a conductance increase. This response was in part sensitive to 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and in part sensitive to d-2-amino-5-phosphonovalerate (d-AP5) and Mg2+ ions. At depolarizing potentials, in the presence of CNQX and d-AP5, l-AP4 caused excitation by depressing K+ currents, mimicking the metabotropic action of glutamate. This indicates that the action of l-AP4 is mediated by three different receptor types: N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors, and glutamatergic metabotropic receptors. The l-AP4 response persisted in solutions containing low Ca2+ and high Mg2+ concentrations or 100 - 200 microM Cd2+, suggesting that it is independent of extracellular Ca2+. We were unable to identify any substance other than quisqualate capable of sensitizing the l-AP4 action. This effect also occurred when quisqualate was applied in Ca2+-free solution or in solutions containing low concentrations of Na+ or Cl-. Sensitization of l-AP4 responses by quisqualate was not observed in acutely dissociated pyramidal cells recorded by means of the whole-cell recording mode, although ionotropic quisqualate responses were present. Sensitization was readily reversed by short applications of the endogenous excitatory amino acids glutamate, aspartate and homocysteate at concentrations of 10 - 100 microM. Our data are consistent with the hypothesis that the excitatory action of l-AP4 results from a Ca2+-independent release of endogenous excitatory amino acids from some presynaptic neuronal or glial site.

Journal Article↗