Serotonergic hyperinnervation and effective serotonin blockade in an FGF receptor developmental model of psychosis

SCHIZOPHRENIA RESEARCH

卷:113

Article

Klejbor, Ilona^1,2  Kucinski, Aaron¹  Wersinger, Scott R.³  Corso, Thomas^1,7  Spodnik, Jan H.²  Dziewiatkowski, Jerzy²  Morys, Janusz²  Hesse, Renae A.³  Rice, Kenner C.^5,6  Miletich, Robert⁴  Stachowiak, Ewa K.¹  Stachowiak, Michal K.^1,2 

[1] SUNY Buffalo, Dept Pathol & Anat Sci, Buffalo, NY 14214 USA

[2] Med Univ Gdansk, Dept Anat & Neurobiol, Gdansk, Poland

[3] SUNY Buffalo, Dept Psychol, Buffalo, NY 14214 USA

[4] SUNY Buffalo, Dept Nucl Med, Buffalo, NY 14214 USA

[5] Natl Inst Drug Abuse, Bethesda, MD USA

[6] NIAAA, Bethesda, MD USA

[7] Lake Erie Coll Osteopath Med, Dept Biochem, Erie, PA 16509 USA

关键词: FGF receptor-1;    Midbrain dopamine neurons;    5-HT2A receptor;    Atypical antipsychotics;    Sensory gating;    Social interaction;   

DOI  :  10.1016/j.schres.2009.06.006

来源: Elsevier

【 摘 要 】

The role of fibroblast growth factor receptors (FGFR) in normal brain development has been well-documented in transgenic and knock-out mouse models. Changes in FGF and its receptors have also been observed in schizophrenia and related developmental disorders. The current study examines a transgenic th(tk-)/th(tk-) mouse model with FGF receptor signaling disruption targeted to dopamine (DA) neurons, resulting in neurodevelopmental, anatomical, and biochemical alterations similar to those observed in human schizophrenia. We show in th(tk-)/th(tk-) mice that hypoplastic development of DA systems induces serotonergic hyperinnervation of midbrain DA nuclei, demonstrating the co-developmental relationship between DA and 5-HT systems. Behaviorally, th(tk-)/th(tk-) mice displayed impaired sensory gaiting and reduced social interactions correctable by atypical antipsychotics (AAPD) and a specific 5-HT2A antagonist, M100907. The adult onset of neurochemical and behavioral deficits was consistent with the postpubertal time course of psychotic symptoms in schizophrenia and related disorders. The spectrum of abnormalities observed in th(tk-)/th(tk-) mice and the ability of AAPD to correct the behavioral deficits consistent with human psychosis suggests that midbrain 5-HT-2A-controlling systems are important loci of therapeutic action. These results may provide further insight into the complex multi-neurotransmitter etiology of neurodevelopmental diseases such autism, bipolar disorder, Asperger's Syndrome and schizophrenia. (C) 2009 Elsevier B.V. All rights reserved.

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