Serotonergic hyperinnervation and effective serotonin blockade in an FGF receptor developmental model of psychosis.
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-HT2A-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.
Klejbor
Ilona
I
Department of Pathology and Anatomical Sciences, SUNY, Buffalo, NY 14214, USA.
Kucinski
Aaron
A
Wersinger
Scott R
SR
Corso
Thomas
T
Spodnik
Jan H
JH
Dziewiatkowski
Jerzy
J
Moryś
Janusz
J
Hesse
Renae A
RA
Rice
Kenner C
KC
Miletich
Robert
R
Stachowiak
Ewa K
EK
Stachowiak
Michal K
MK
D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001522:Behavior, Animal; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005464:Fluorobenzenes / Q000627:therapeutic use*; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000235:genetics; D006120:Grooming / Q000502:physiology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000235:genetics; D010880:Piperidines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D013216:Reflex, Startle / Q000235:genetics; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D012919:Social Behavior
D014150:Antipsychotic Agents; D005464:Fluorobenzenes; D010880:Piperidines; D017468:Receptors, Fibroblast Growth Factor; D012702:Serotonin Antagonists; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D011505:Protein-Tyrosine Kinases; C079049:volinanserin