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Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype.

Abstract : Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT2B) receptor stop-codon (i.e. HTR2B Q20*) was reported to segregate with severely impulsive individuals, while 5-HT2B mutant (Htr2B-/-) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT2B receptors in mice subjected to a comprehensive series of behavioral tests screening for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative and cognitive symptom-clusters of schizophrenia were affected in Htr2B-/- mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions and in learning and memory processes. In addition, Htr2B-/- mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophrenic-like phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT2B in the neurobiology of psychotic disorders.
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Pothitos Pitychoutis, Arnauld Belmer, Imane Moutkine, Joëlle Adrien, Luc Maroteaux. Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology., 2015, 40 (12), pp.2764-73. ⟨10.1038/npp.2015.126.⟩. ⟨inserm-01149629⟩

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