Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Psychopharmacology Année : 2017

Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice.

Résumé

The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders. OBJECTIVE: Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia. We tested PTPRG -/- , PTPRZ -/- , and wild-type male mice for effects on social behavior, forced swim test, and anxiety, as well as on regional brain neurochemistry. RESULTS: The most notable behavioral consequences of PTPRG gene inactivation were reduced immobilization in the forced swim test, suggestive of some negative symptoms of schizophrenia. By contrast, PTPRZ -/- mice demonstrated marked social alteration with increased aggressivity, reminiscent of some positive symptoms of schizophrenia. Both knockouts showed elevated dopamine levels in prefrontal cortex, hippocampus, and most particularly amygdala, but not striatum, accompanied by reduced dopamine beta hydroxylase activity only in amygdala. In addition, PTPRG KO elicited a distinct increase in hippocampal serotonin level not observed in PTPRZ KO. CONCLUSION: PTPRG and PTPRZ gene loss therefore induces distinct patterns of behavioral change and region-specific alterations in neurotransmitters, highlighting their usefulness as models for neuropsychiatric disorder mechanisms and making these receptors attractive targets for therapy.
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hal-01443579 , version 1 (23-01-2017)

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Arnaud Cressant, Veronique Dubreuil, Jing Kong, Thorsten Manfred Kranz, Françoise Lazarini, et al.. Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice.. Psychopharmacology, 2017, 234 (4), pp. 575-587. ⟨10.1007/s00213-016-4490-8⟩. ⟨hal-01443579⟩
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