Altered dopaminergic innervation and amphetamine response in adult Otx2 conditional mutant mice.
Here, we have investigated the neurological consequences of restricted inactivation of Otx2 in adult En1(cre/+); Otx2(flox/flox) mice. In agreement with the crucial role of Otx2 in midbrain patterning, the mutants had a substantial reduction in tyrosine hydroxylase containing neurons. Although the reduction in the number of DAergic neurons was comparable between the SNc and the VTA, we found an unexpected selectivity in the deinnervation of the terminal fields affecting preferentially the ventral striatum and the olfactory tubercle. Interestingly, the mutants showed no abnormalities in exploratory activity or motor coordination. However, the absence of normal DA tone generated significant alterations in DA D1-receptor signalling as indicated by increased mutant striatal levels of phosphorylated DARPP-32 and by an altered motor response to amphetamine. Therefore, we suggest that the En1(cre/+); Otx2(flox/flox) mutant mouse model represents a genetic tool for investigating molecular and behavioural consequences of developmental neuronal dysfunction in the DAergic system.
Borgkvist
Anders
A
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, S-17177 Stockholm, Sweden.
Puelles
Eduardo
E
Carta
Manolo
M
Acampora
Dario
D
Ang
Siew-Lan
SL
Wurst
Wolfgang
W
Goiny
Michel
M
Fisone
Gilberto
G
Simeone
Antonio
A
Usiello
Alessandro
A
D000662:Amphetamines / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D045442:Rotarod Performance Test; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000662:Amphetamines; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C080330:En1 protein, mouse; D018398:Homeodomain Proteins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; C497929:Ppp1r1b protein, mouse; D017447:Receptors, Dopamine D1; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine