Fibroblast growth factor receptor signaling affects development and function of dopamine neurons - inhibition results in a schizophrenia-like syndrome in transgenic mice.
Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk-)/th(tk-) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro-striatal DA system. Paradoxically, the th(tk-)/th(tk-) mice had increased levels of DA, homovanilic acid and 3-methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk-)/th(tk-) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia-like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA-mediated behavior.
Klejbor
Ilona
I
Molecular and Structural Neurobiology and Gene Therapy Program, Departments of Pathology and Anatomical Sciences and Chemistry, SUNY Buffalo, New York 14214, USA.
Myers
Jason M
JM
Hausknecht
Kathy
K
Corso
Thomas D
TD
Gambino
Angelo S
AS
Morys
Janusz
J
Maher
Pamela A
PA
Hard
Robert
R
Richards
Jerry
J
Stachowiak
Ewa K
EK
Stachowiak
Michal K
MK
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049108:Cell Enlargement; D004195:Disease Models, Animal; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics; D013378:Substantia Nigra / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D017557:Ventral Tegmental Area / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology
D050483:Dopamine Plasma Membrane Transport Proteins; D016222:Fibroblast Growth Factor 2; D014446:Tyrosine 3-Monooxygenase; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; C001746:3-methoxytyramine; D004298:Dopamine; D006719:Homovanillic Acid