Inflammation and pediatric epilepsy : effects on epileptogenesis and psychiatric comorbidities

Inflammation and pediatric epilepsy : effects on epileptogenesis and psychiatric comorbidities

Main Research Projects

inflammation and pediatric epilepsyEpilepsy is one of the most prevalent major childhood neurologic disorders, affecting 0.5 to 1.0 % of children up to 16 years of age, and the majority of adults with epilepsy had childhood onset. Epilepsy is a heterogeneous entity represented by various epilepsy syndromes (ILAE 2011) with various etiologies. The epilepsy syndrome is not only characterized by the type of seizure and EEG findings. Cognitive and psychiatric disorders are also part of the syndrome. These include cognitive involvement, autism, attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, and psychotic disorders in both children and adults.

A recent breakthrough in epilepsy research concerns the links between brain inflammation and seizures. Clinical and neuropathological evidence obtained in adult patients suggest that inflammation could play also a central role in seizure disorders without infectious or immune-mediated etiology. In pediatric epilepsy, the effects of inflammation on seizure genesis are not well understood. In the first part of this project we analyze in animal models of juvenile and adult epilepsy: 1) The effects of central and peripheral injections of the TLR3 agonist PolyI:C and TLR4 agonist LPS on epileptogenesis and ictogenesis and 2) the effects of ischemia-induced inflammation on seizure severity.

Interestingly, reciprocal interactions between the immune system and the brain have also recently attracted considerable attention regarding the role of the immune system in neuropsychiatric diseases, and especially in major depression. Because inflammation appears as a common link between epilepsy and depression, one might hypothesize that pro-inflammatory cytokines released during the epileptic process could regulate component of the serotoninergic system, and consequently, diminish raphe-hippocampal/frontal cortex serotonergic transmission.

Because the links between inflammation and depression are not known in pediatric epilepsy, the aim of our second project is: 1) through clinical studies to analyse whether anxiety or depression may be concomitant or pre-existing state in pediatric epilepsy; 2) through studies in in vivo and in vitro models: a- to analyse the effects of pro-inflammatory cytokines on the traffic of the 5HT1A receptor and serotonin transporter SERT, two major regulators of serotonin homeostasis), b- to analyse whether anti-inflammatory molecules can impact on serotoninergic markers and depression.

The research group 2015

Tania Vitalis, CR1, Researcher, Inserm
Pascal Dournaud, CR1, Researcher, Inserm
Stéphane Auvin, PUPH, Researcher, APHP-Paris VII
Zsolt Csaba, IR2, Engineer, Inserm
Stéphane Peineau, Research Associate, Researcher, University of Bristol
Nina Dupuis, Post-Doc, Researcher, Industrie
Béatrice Desnous, student, PhD student, Université Paris VII
Aurore Famy, student, PhD student, Université Paris VII
Desprairies Camille, student, Master, Université Paris VII
Julie Enderlin, student, Master, EPHE

Ten major publications during the last 5 years

Trans-modulation of the somatostatin type 2A receptor trafficking by Insulin-regulated aminopeptidase decreases seizures. Dimitri De Bundel*, Assia Fafouri*, Zsolt Csaba*, Ellen Loyens, Sophie Lebon, Vincent El Ghouzzi, Stéphane Peineau, Guilan Vodjdani, Foteini Kiagiadaki, Najat Aourz, Jessica Coppens, Laura Walrave, Jeanelle Portelli, Patrick Vanderheyden, Siew Yeen Chai, Kyriaki Thermos, Véronique Bernard, Graham Collingridge, Stéphane Auvin, Pierre Gressens, Ilse Smolders** and Pascal Dournaud**. J Neurosci. 2015 Aug 26;35(34):11960-75

Dymeclin deficiency induces postnatal microcephaly, hypomyelination and neuronal trafficking defects. NINA DUPUIS*, ASSIA FAFOURI*, Aurélien Bayot, Manoj Kumar, Tifenn Lecharpentier, Gareth Ball, David Edwards, Véronique Bernard, Pascal Dournaud, Séverine Drunat, Marie Vermelle, Catheline Vilain, Marc Abramowicz, Julie Désir, Jacky Bonaventure, Gaelle Boncompain, ZSOLT CSABA, Franck Perez, Sandrine Passemard, PIERRE GRESSENS, Vincent El Ghouzzi. Hum Mol Genet. 2015 2015 May 15;24(10):2771-83

Antiictogenic and antiepileptogenic properties of brivaracetam in mature and immature rats. Nina Dupuis, Alain Matagne, Ludovicus Staelens, Pascal Dournaud, Béatrice Desnous, Pierre Gressens and Stéphane Auvin. Epilepsia 2015 May;56(5):800-5.

Serotonin receptor 3A controls interneuron migration into the neocortex. Murthy S, Niquille M, Hurni N, Limoni G, Frazer S, Chameau P, van Hooft JA, VITALIS T, Dayer A. Nat Commun. 2014 Nov 20;5:5524.

Somatostatin receptors type 2 and 5 expression and localization during human pituitary development. PEINEAU S, Guimiot F, CSABA Z, Jacquier S, FAFOURI A, Schwendimann L, de Roux N, Schulz S, GRESSENS P, AUVIN S, DOURNAUD P. Endocrinology. 2014 Jan;155(1):33-9.

Maternal immune activation promotes hippocampal kindling epileptogenesis in mice. Pineda E, Shin D, You SJ, AUVIN S, Sankar R, Mazarati A. Ann Neurol. 2013 Jul;74(1):11-9.

G protein-coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation-induced sensitization to excitotoxic neurodegeneration. Degos V, PEINEAU S, Nijboer C, Kaindl AM, Sigaut S, Favrais G, Plaisant F, Teissier N, Gouadon E, Lombet A, Saliba E, Collingridge GL, Maze M, Nicoletti F, Heijnen C, Mantz J, Kavelaars A, Gressens P. Ann Neurol. 2013 May;73(5):667-78.

Novel animal models of pediatric epilepsy. AUVIN S, Pineda E, Shin D, GRESSENS P, Mazarati A. Neurotherapeutics. 2012 Apr;9(2):245-61.

Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Kaindl AM, Degos V, PEINEAU S, Gouadon E, Chhor V, Loron G, Le Charpentier T, Josserand J, Ali C, Vivien D, Collingridge GL, Lombet A, Issa L, Rene F, Loeffler JP, Kavelaars A, Verney C, Mantz J, Gressens P. Ann Neurol. 2012 Oct;72(4):536-49

The Jak/STAT pathway is involved in synaptic plasticity. Nicolas CS*, PEINEAU S*, Amici M, Csaba Z, Fafouri A, Javalet C, Collett VJ, Hildebrandt L, Seaton G, Choi SL, Sim SE, Bradley C, Lee K, Zhuo M, Kaang BK, Gressens P, Dournaud P, Fitzjohn SM, Bortolotto ZA, Cho K, Collingridge GL. Neuron. 2012 Jan 26;73(2):374-90.

Serotonin 3A receptor subtype as an early and protracted marker of cortical interneuron subpopulations. Vucurovic K, Gallopin T, Ferezou I, Rancillac A, Chameau P, van Hooft JA, Geoffroy H, Monyer H, Rossier J, VITALIS T. Cereb Cortex. 2010 Oct;20(10):2333-47