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Séminaire - Marco Sassoè-PognettoDystroglycan is a major organizer of subtypes of GABA synapses

Abstract :

GABAergic inhibition may be “the real essence” in neuronal computation. Practically all neurons in the brain express GABA receptors, which occur in several different subunit combinations and control many crucial aspects of neural function. Changes in GABAergic transmission contribute to the etiology of prominent brain disorders, including epilepsy, anxiety, and schizofrenia. Therefore, the mechanisms that regulate the development and maturation of GABA synapses have important consequences for brain function and disease.
Research over the last two decades has revealed an extraordinary diversity in the anatomical and molecular organization of GABA circuits. We are just starting to appreciate the physiological importance of this diversity, and how it is determined during brain development. In this perspective, I will focus on the evidence that has become available from the analysis of genetic loss-of-function models, i.e. mutant mice lacking crucial molecular constituents of synaptic specializations.
Recent investigations have revealed that proteins in the synaptic cleft act as divalent ligands linking pre- and postsynaptic transmembrane components. Accordingly, the synaptic extracellular matrix can be regarded as the site in which secreted factors and cell adhesion molecules mediate trans-synaptic interactions that may contribute to encode synaptic specificity. An exciting concept emerging from these studies is that GABAergic synaptogenesis depends on multiple pathways, linked into signaling complexes that act synergistically to coordinate synapse development.


Selected publications

Pharmacological reversion of sphingomyelin-induced dendritic spine anomalies in a Niemann Pick disease type A mouse model. Arroyo AI, Camoletto PG, Morando L, Sassoe-Pognetto M, Giustetto M, Van Veldhoven PP, Schuchman EH, Ledesma MD. EMBO Mol Med. 2014 Jan 21. [Epub ahead of print]

Differential regulation of neurexin at glutamatergic and GABAergic synapses.
Pregno G, Frola E, Graziano S, Patrizi A, Bussolino F, Arese M, Sassoè-Pognetto M.
Front Cell Neurosci. 2013 Apr 4;7:35. doi: 10.3389/fncel.2013.00035. eCollection 2013.

Synaptic competition sculpts the development of GABAergic axo-dendritic but not perisomatic synapses. 
Frola E, Patrizi A, Goetz T, Medrihan L, Petrini EM, Barberis A, Wulff P, Wisden W, Sassoè-Pognetto M. PLoS One. 2013;8(2):e56311. doi: 10.1371/journal.pone.0056311. Epub 2013 Feb 14.

Morphine withdrawal produces ERK-dependent and ERK-independent epigenetic marks in neurons of the nucleus accumbens and lateral septum. Ciccarelli A, Calza A, Santoru F, Grasso F, Concas A, Sassoè-Pognetto M, Giustetto M. Neuropharmacology. 2013 Jul;70:168-79. doi: 10.1016/j.neuropharm.2012.12.010. Epub 2013 Jan 21.

Organization of GABAergic synaptic circuits in the rat ventral tegmental area.
Ciccarelli A, Calza A, Panzanelli P, Concas A, Giustetto M, Sassoè-Pognetto M. PLoS One. 2012;7(10):e46250. doi: 10.1371/journal.pone.0046250. Epub 2012 Oct 8.

Early formation of GABAergic synapses governs the development of adult-born neurons in the olfactory bulb.
Pallotto M, Nissant A, Fritschy JM, Rudolph U, Sassoè-Pognetto M, Panzanelli P, Lledo PM. J Neurosci. 2012 Jun 27;32(26):9103-15. doi: 10.1523/JNEUROSCI.0214-12.2012.

Cholesterol loss during glutamate-mediated excitotoxicity. Sodero AO, Vriens J, Ghosh D, Stegner D, Brachet A, Pallotto M, Sassoè-Pognetto M, Brouwers JF, Helms JB, Nieswandt B, Voets T, Dotti CG. EMBO J. 2012 Apr 4;31(7):1764-73. doi: 10.1038/emboj.2012.31. Epub 2012 Feb 17.

Scientific focus :

Recently, I have focused on the question of how synaptic specificity may be encoded by selective trans-synaptic interactions between pre- and postsynaptic molecular constituents.
Recent research in my laboratory has contributed to reveal an unexpected complexity in the molecular organization of GABA synapses (Saiepour et al., 2010; Hoon et al., 2011; Patrizi et al., 2012), emphasizing the importance of novel cataloguing tools that could be used to decipher their molecular and functional heterogeneity (Sassoè-Pognetto, 2011; Sassoè-Pognetto et al., 2011). By studying different lines of genetically modified mice, we also discovered that GABAergic signaling has a selective role in regulating synapse development in distinct subcellular compartments (Fritschy et al., 2006; Patrizi et al., 2008; Wulff et al., 2009). Using a similar approach, we have investigated how GABAergic transmission finely tunes olfactory bulb circuits (Lagier et al., 2007), and how it regulates the integration of adult-generated neurons in pre-existing synaptic circuits (Panzanelli et al., 2009; Pallotto et al., 2012).