GABAA receptor; phosphorylation; SUMOylation; inhibitory neurotransmission; synaptic plasticity; Lithium; bipolar disorder; adult neurogenesis
Tyagarajan Shiva K, Ghosh Himanish, Yévenes Gonzalo E, Imanishi Susumu Y, Zeilhofer Hanns Ulrich, Gerrits Bertran, Fritschy Jean-Marc (2013), Extracellular signal-regulated kinase and glycogen synthase kinase 3β regulate gephyrin postsynaptic aggregation and GABAergic synaptic function in a calpain-dependent mechanism., in The Journal of biological chemistry
, 288(14), 9634-47.
Pallotto Marta, Nissant Antoine, Fritschy Jean-Marc, Rudolph Uwe, Sassoè-Pognetto Marco, Panzanelli Patrizia, Lledo Pierre-Marie (2012), Early formation of GABAergic synapses governs the development of adult-born neurons in the olfactory bulb., in The Journal of neuroscience : the official journal of the Society for Neuroscience
, 32(26), 9103-15.
Deprez Francine, Zattoni Michela, Mura Maria Luisa, Frei Karl, Fritschy Jean-Marc (2011), Adoptive transfer of T lymphocytes in immunodeficient mice influences epileptogenesis and neurodegeneration in a model of temporal lobe epilepsy., in Neurobiology of disease
, 44(2), 174-84.
Panzanelli Patrizia, Gunn Benjamin G, Schlatter Monika C, Benke Dietmar, Tyagarajan Shiva K, Scheiffele Peter, Belelli Delia, Lambert Jeremy J, Rudolph Uwe, Fritschy Jean-Marc (2011), Distinct mechanisms regulate GABAA receptor and gephyrin clustering at perisomatic and axo-axonic synapses on CA1 pyramidal cells., in The Journal of physiology
, 589(Pt 20), 4959-80.
Duveau Venceslas, Madhusudan Amrita, Caleo Matteo, Knuesel Irene, Fritschy Jean-Marc (2011), Impaired reelin processing and secretion by Cajal-Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy., in Hippocampus
, 21(9), 935-44.
Duveau Venceslas, Laustela Simon, Barth Lydia, Gianolini Francesca, Vogt Kaspar E, Keist Ruth, Chandra Dev, Homanics Gregg E, Rudolph Uwe, Fritschy Jean-Marc (2011), Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis., in The European journal of neuroscience
, 34(3), 362-73.
Tyagarajan Shiva K, Ghosh Himanish, Harvey Kirsten, Fritschy Jean-Marc (2011), Collybistin splice variants differentially interact with gephyrin and Cdc42 to regulate gephyrin clustering at GABAergic synapses., in Journal of cell science
, 124(Pt 16), 2786-96.
Witschi R, Punnakkal P, Paul J, Walczak JS, Cervero F, Fritschy JM, Kuner R, Keist R, Rudolph U, Zeilhofer HU (2011), Presynaptic alpha 2-GABA(A) Receptors in Primary Afferent Depolarization and Spinal Pain Control, in JOURNAL OF NEUROSCIENCE
, 31(22), 8134-8142.
Pallotto M., Nissant A., Fritschy J.-M., Rudolph U., Sassoè-Pognetto M., Panzanelli P., Lledo P.M., Early formation of GABAergic synapses governs the development of adult-born neurons in the olfactory bulb., in Journal of Neuroscience
Fritschy Jean-Marc, Panzanelli Patrizia, Tyagarajan Shiva K, Molecular and functional heterogeneity of GABAergic synapses., in Cellular and molecular life sciences : CMLS
Paul J., Zeilhofer H.U., Fritschy J.-M., Selective distribution of GABAA receptor subtypes in mouse spinal dorsal horn neurons and primary afferents., in Journal of Comparative Neurology
Marowsky A., Rudolph U., Fritschy J.-M., Arand M., Tonic inhibition in the basolateral amygdala is mediated by 3 subunit-containing GABAA receptors., in Journal of Neuroscience
1. SummaryInhibitory neurotransmission in the CNS plays a crucial role in the control of neuronal excitability and network synchronization, thereby contributing to the emergence of higher brain functions. It is mediated mainly by GABAAR, which belong to the family of ligand-gated ion channels and are assembled from a large family of subunits. GABAAR are a major target for drugs used in the clinical management of anxiety, sleep disorders, muscle spasms, and epilepsy. In addition, dysfunctions of the GABAergic system likely contribute to the pathophysiology of prevalent psychiatric diseases, including autism and schizophrenia. It is the long-term goal of my laboratory to elucidate the mechanisms governing the formation and plasticity of GABAergic local circuits in order to provide a better understanding of the pathophysiology of CNS diseases and design novel avenues for therapeutic intervention.Proper function of synapses depends on the appropriate targeting and localization of effector proteins in presynaptic terminals and at postsynaptic sites. This is ensured by scaffolding proteins, which built complexes of functionally related proteins and anchor them at the presynaptic active zone and at the postsynaptic density. In GABAergic synapses, the main scaffolding protein is gephyrin, a cytoskeletal protein forming aggregates responsible for anchoring of GABAAR (and glycine receptors) at postsynaptic sites. Our past work has shown that the synaptic localization of gephyrin is dependent on the presence of GABAAR, suggesting regulation by signaling mechanisms. Recently (see Own Contributions), we have identified two phosphorylation sites on gephyrin that regulate the formation and the size of postsynaptic clusters, and thereby the strength of GABAergic transmission. Furthermore, we have shown that LiCl, a drug used for the treatment of bipolar disorders, strongly influences gephyrin clustering by blocking its phosphorylation. Finally, we also have preliminary evidence for bidirectional regulation of gephyrin clustering by SUMOylation. Collectively, these findings suggest that intracellular signaling cascades (e.g., protein kinases and phosphatases activated by second messengers) regulate GABAergic transmission by acting on the gephyrin scaffold. The general aim of this research proposal is to explore the molecular mechanisms underlying gephyrin regulation and to determine how this regulation impacts the formation and plasticity of GABAergic synapses. To this end, we will pursue three major lines of research: First, we will further characterize gephyrin phosphorylation and its role for the control of clustering at postsynaptic sites. We will also analyze how gephyrin phosphorylation influences its interactions with GABAAR and their cell-surface dynamics. Second, we will investigate the effects of gephyrin SUMOylation on its aggregation, trafficking, and postsynaptic clustering, and explore whether SUMOylation and phosphorylation of gephyrin are functionally inter-related. Third, using in vivo transfection of newborn neurons with lentiviral vectors, we will determine the functional consequences of chronic perturbations of gephyrin phosphorylation and SUMOylation on GABAergic synapse formation and plasticity in adult CNS. This in vivo part will be complemented by experiments aiming at identifying novel therapeutic approaches for the treatment of mood-disorders, based on the effect of LiCl on gephyrin clustering.This project relies on our long-standing expertise on the functional organization of GABAergic neurotransmission. It is conceptually highly innovative and challenges traditional views about the role of gephyrin postsynaptic scaffolds for regulating plasticity and formation of GABAergic synapses. By using a multidisciplinary approach combining molecular biology, biochemistry, cell biology, and in vivo experiments, we expect to uncover novel molecular mechanisms underlying activity-dependent regulation of GABAergic synapses by intracellular signaling cascades. Furthermore, by elucidating how the regulation of gephyrin clustering leads to structural and functional adaptations of the GABAergic system and participates to the pharmacological action of LiCl, our project opens new avenues for therapeutic interventions, based on the modulation of signaling cascades regulating GABAergic transmission.