N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice

David Marian Otte (1) , Britta Sommersberg (1) , Alexei Kudin (1) , Catalina Guerrero (1) , Önder Albeiram (1) , Michaela Filiou (1) , Pamela Frisch (1) , Öznur Yilmaz (1) , Eva Drews (1) , C.W. Turck (1) , Andras Bilkei-Gorzo (1) , Wolfram Kunz (1) , Heinz Beck (1) , Andreas Zimmer (1)

1 Department of Molecular Psychiatry

Genetic studies have implicated the evolutionary novel, anthropoid primate-specific gene locus G72/G30 in psychiatric diseases. This gene encodes the protein LG72 that has been discussed to function as a putative activator of the peroxisomal enzyme D-amino-acid-oxidase (DAO) and as a mitochondrial protein. We recently generated "humanized" BAC transgenic mice (G72Tg) expressing G72 transcripts in cells throughout the brain. These mice exhibit several behavioral phenotypes related to psychiatric diseases. Here we show that G72Tg mice have a reduced activity of mitochondrial complex I, with a concomitantly increased production of reactive oxygen species. Affected neurons display deficits in short-term plasticity and an impaired capability to sustain synaptic activity. These deficits lead to an impairment in spatial memory, which can be rescued by pharmacological treatment with the glutathione precursor N-acetyl cysteine (NAC). Our results implicate LG72-induced mitochondrial and synaptic defects as a possible pathomechanism of psychiatric disorders.

Mots clés: Animal models; Cognition; Behavioral Science; Biological Psychiatry; G72/DAOA; Schizophrenia; spatial learning

David Marian Otte, Britta Sommersberg, Alexei Kudin, Catalina Guerrero, Önder Albeiram, et al.. N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice. Neuropsychopharmacology, 2011, ⟨10.1038/npp.2011.109⟩. ⟨hal-00655433⟩