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Cognition- and circuit-based dysfunction in a mouse model of 22q11.2 microdeletion syndrome: effects of stress

  • Tripathi, Anushree1, 2
  • Spedding, Michael3, 4
  • Schenker, Esther3
  • Didriksen, Michael5
  • Cressant, Arnaud6, 7
  • Jay, Therese M.1
  • 1 Institute of Psychiatry and Neurosciences of Paris (IPNP), INSERM U1266, Pathophysiology of Psychiatric Disorders, Université de Paris, Paris, F-75014, France , Paris (France)
  • 2 Umeå University, Umeå, 90187, Sweden , Umeå (Sweden)
  • 3 Institut de Recherches Servier, Croissy, France , Croissy (France)
  • 4 Spedding Research Solutions SAS, 6 rue Ampere, 78110 Le Vesinet, France, Le Vesinet, 78110, France , Le Vesinet (France)
  • 5 H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark , Valby (Denmark)
  • 6 France [email protected] SAS, 13 rue des moulins neufs, Saint-Prest, 28300, France , Saint-Prest (France)
  • 7 UMR 1253, iBrain, Université de Tours, Inserm, Tours, France , Tours (France)
Published Article
Translational Psychiatry
Nature Publishing Group UK
Publication Date
Jan 28, 2020
DOI: 10.1038/s41398-020-0687-z
Springer Nature


Genetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to dysfunction of the prefrontal cortex (PFC). We used behavioral (n = 10 per genotype), electrophysiological (n = 7 per genotype per group), and neuroanatomical (n = 5 per genotype) techniques to investigate schizophrenia-related pathology of Df(h22q11)/+ mice, which showed a significant decrease in the total number of parvalbumin positive interneurons in the medial PFC. The Df(h22q11)/+ mice when tested on PFC-dependent behavioral tasks, including gambling tasks, perform significantly worse than control animals while exhibiting normal behavior on hippocampus-dependent tasks. They also show a significant decrease in hippocampus-medial Prefrontal cortex (H-PFC) synaptic plasticity (long-term potentiation, LTP). Acute platform stress almost abolished H-PFC LTP in both wild-type and Df(h22q11)/+ mice. H-PFC LTP was restored to prestress levels by clozapine (3 mg/kg i.p.) in stressed Df(h22q11)/+ mice, but the restoration of stress-induced LTP, while significant, was similar between wild-type and Df(h22q11)/+ mice. A medial PFC dysfunction may underlie the negative and cognitive symptoms in human 22q11 deletion carriers, and these results are relevant to the current debate on the utility of clozapine in such subjects.

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