Hippocampal GABAergic Neurons are Susceptible to Amyloid-β Toxicity in vitro and are Decreased in Number in the Alzheimer's Disease TgCRND8 Mouse Model

Article type: Research Article

Authors: Krantic, Slavica^{a; b; *} | Isorce, Nathalie^b | Mechawar, Naguib^b | Davoli, Maria Antonietta^b | Vignault, Erika^b | Albuquerque, Marilia^b | Chabot, Jean-Guy^b | Moyse, Emmanuel^c | Chauvin, Jean-Pierre^d | Aubert, Isabelle^{e; f} | McLaurin, JoAnne^{f; g} | Quirion, Rémi^b

Affiliations: [a] Institut de Neurobiologie de la Méditerranée (INMED), U901, Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille, France | [b] Douglas Mental Health University Institute (DMHUI), Department of Psychiatry, McGill University, Verdun (Montréal), QC, Canada | [c] Physiologie Neurovégétative (PNV), Université Aix-Marseille III Paul Cézanne, UMR 6231 CNRS-USC 2027 INRA, Marseille, France | [d] Institut de biologie du développement de Marseille (IBDM), Centre de Recherche Scientifique (CNRS), UMR 6216, Marseille, France | [e] Sunnybrook Health Sciences Centre, Toronto, ON, Canada | [f] Department Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada | [g] Tanz Center for Research in Neurodegenerative Diseases, Toronto, ON, Canada

Correspondence: [*] Correspondence to: Slavica Krantic, PhD, DMHUI, Research Center, 6875 LaSalle Boulevard, Verdun (Montreal), H4H 1R3 QC, Canada. Tel.: +1 514 761 6131; Ext: 2482; Fax: +1 514 762 3034; E-mail: slavica.krantic@douglas.mcgill.ca.

Abstract: The relevance of γ-amino-butyric acid (GABA)-ergic dysfunctions in the pathology of Alzheimer's disease (AD) remains a matter of debate. In the present study, we characterized the toxicity of amyloid-β (Aβ) on hippocampal GABAergic neurons both in vivo and in vitro. In the TgCRND8 mouse model of AD, we found a significant decrease in the number of hippocampal neurons immunoreactive for glutamate decarboxylase 67 (GAD67), the enzyme synthesizing GABA. This decrease, which was specific for hippocampal CA1-3 fields, was observed at 6 months of age, long after the overproduction of soluble Aβ42 (between 2 and 4 months) and accumulation of insoluble Aβ into amyloid plaques (between 4 and 6 months). In vitro, neurotoxicity was observed in primary hippocampal cultures 72 h following the addition of Aβ42 solutions containing a mixture of soluble oligomers. Taken together, our results suggest that when cultured and exposed to Aβ in vitro, GABAergic neurons are susceptible to Aβ42 neurotoxicity. However, in TgCRND8 mice, the number of GABAergic neurons is not altered up to 6 months, in spite of the massive Aβ load. Combined with the previously reported increased sensitivity to seizures observed in younger (1.5–2 month-old) TgCRND8 mice, it is likely that Aβ toxicity leads to GABAergic neuron dysfunction prior to their losses at a later stage.

Keywords: Alzheimer's disease, amyloid beta-protein, GABAergic neurons, hippocampus, neuronal cell death, primary cell culture, TgCRND8 mice

DOI: 10.3233/JAD-2011-110830

Journal: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 293-308, 2012