Premium
Fibroblast growth factor receptor signaling affects development and function of dopamine neurons – inhibition results in a schizophrenia‐like syndrome in transgenic mice
Author(s) -
Klejbor Ilona,
Myers Jason M.,
Hausknecht Kathy,
Corso Thomas D.,
Gambino Angelo S.,
Morys Janusz,
Maher Pamela A.,
Hard Robert,
Richards Jerry,
Stachowiak Ewa K.,
Stachowiak Michal K.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03754.x
Subject(s) - substantia nigra , pars compacta , tyrosine hydroxylase , ventral tegmental area , endocrinology , striatum , dopamine , medicine , biology , fibroblast growth factor receptor 1 , dopaminergic , neuroscience , receptor , fibroblast growth factor
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.