In vivo effects of anti-glutamate decarboxylase 65 antibodies on the hippocampus
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1
Université de Mons - Service de Neurosciences, Service de Neurosciences, Belgium
Anti-GAD 65 antibodies have been detected in patients suffering from various pathologies such as stiff person syndrome, cerebellar ataxia, limbic encephalitis and type 1 diabetes. It binds the smaller isoform of GAD that converts the excitatory glutamate into inhibitory GABA at the level of GABAergic neurons. It has been proved that in vivo injections of anti-GAD65 antibodies induce motor deficits (Hansen et al., 2013), increase of extracellular glutamate concentration (Manto et al., 2011), anxious behavior (Geis et al., 2011) and also alteration of spatial strategies and cognitive capacities (Hampe et al., 2013). These effects are epitope specific. It has been demonstrated that b78 recognizes an epitope located at the C-terminus (512-540) while the b96.11 target is situated in the center of the protein (308-365). These two specific anti-GAD65 human monoclonal antibodies derived from a patient with autoimmune polyendocrine syndrome type 1 and have been isolated by the laboratory of Christiane Hampe (University of Washington).
In our laboratory, previous research performed on hippocampal organotypic cultures showed that b78 GAD65 antibodies induce an inhibition of long term potentiation and also a microglial proliferation. So in this study we tend to verify these observations in vivo and to explore more deeply the specific effect of b78 and b96.11 GAD65 antibodies on the hippocampus. To do so, both anti-GAD65 antibodies are slowly injected in the third ventricle of mice. Electrophysiological measurements are conducted to study the long term potentiation of synaptic response on acute hippocampal slices. The inflammatory state of the hippocampus is examined by immunohistochemistry. Furthermore the microdialysis technique will be developed to quantify extracellular glutamate and GABA. Cognitive impairment will be studied by behavioral tests.
Résumé en Français:
Des anticorps anti-glutamate décarboxylase 65 (anti-GAD65) ont été décelés chez des personnes souffrant de diverses pathologies telles que l’encéphalite limbique, le « stiff person syndrome », l’ataxie cérébelleuse ainsi que le diabète de type 1. Ces anticorps sont produits par les patients et ciblent une protéine présente dans le cerveau, la GAD65. Celle-ci assure la conversion du neurotransmetteur excitateur glutamate en neurotransmetteur inhibiteur GABA au niveau des neurones. A l’heure actuelle, plusieurs équipes s’appliquent à mieux comprendre le mécanisme d’action ainsi que les effets de ces anticorps sur le système nerveux. Le laboratoire de Neurosciences de l’UMONS s’est focalisé sur leur incidence dans l’hippocampe, une structure cérébrale indispensable dans le processus de mémorisation.
Samenvatting in het Nederlands:
Anti-glutamate decarboxylase 65 (anti-GAD65) antilichamen werden ontdekt bij personen die lijden aan diverse ziektes zoals limbische encefalitis, het “stiff person syndrome” , de cerebelleuse ataxie en diabetes 1. Deze antilichamen worden aangemaakt door patiënten en zijn gericht op een proteïne aanwezig in de hersenen, de GAD65. Deze staat in voor de omvorming van de neurotransmitter die glutamaat opwekt en de neurotransmitter die GABA belemmert op het niveau van de neuronen. Momenteel proberen meerdere onderzoeksteams het mechanisme en de invloed van deze antilichamen op het zenuwstelsel beter te begrijpen. Het Neurowentenschappelijk Laboratorium van de UMons focust op het voorkomen ervan in de hypocampus, een hersenstructuur die noodzakelijk is voor het geheugenproces.
References
Manto et al., 2011 Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. Orphanet Journal of Rare Diseases 2011, 6:3
Hampe et al., 2013 Monoclonal antibodies to 65 kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rat. Orphanet Journal of Rare Diseases, 8:82
Hansen et al., 2013 Human Stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats. Exp Neurol, 239:202-9
Geis et al., 2011 Human stiff-person syndrome IgG induces anxious behavior in rats. PLoS ONE, 6 (2)
Keywords:
GAD65-antibodies,
Long-Term Potentiation,
Limbic Encephalitis,
Hippocampus,
Memory
Conference:
6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.
Presentation Type:
Poster Presentation
Topic:
Brain and brain diseases: between heredity and environment
Citation:
Brunois
C,
Ris
L,
Paci
P and
Wauters
M
(2016). In vivo effects of anti-glutamate decarboxylase 65 antibodies on the hippocampus.
Conference Abstract:
6th Belgian Brain Congress.
doi: 10.3389/conf.fnagi.2016.03.00067
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Received:
13 Jul 2016;
Published Online:
13 Jul 2016.
*
Correspondence:
PhD. Célestine Brunois, Université de Mons - Service de Neurosciences, Service de Neurosciences, Mons, Hainaut, 7000, Belgium, celestine.brunois@umons.ac.be