Microtubule-associated STOP protein deletion triggers restricted changes in dopaminergic neurotransmission.
The microtubule-associated stable tubule only polypeptide (STOP) protein plays a key-role in neuron architecture and synaptic plasticity. Recent studies suggest that schizophrenia is associated with alterations in the synaptic connectivity. Mice invalidated for the STOP gene display phenotype reminiscent of some schizophrenic-like symptoms, such as behavioral disturbances, dopamine (DA) hyper-reactivity, and possible hypoglutamatergia, partly improved by antipsychotic treatment. In the present work, we examined potential alterations in some DAergic key proteins and behaviors in STOP knockout mice. Whereas the densities of the DA transporter, the vesicular monoamine transporter and the D(1) receptor were not modified, the densities of the D(2) and D(3) receptors were decreased in some DAergic regions in mutant versus wild-type mice. Endogenous DA levels were selectively decreased in DAergic terminals areas, although the in vivo DA synthesis was diminished both in cell bodies and terminal areas. The DA uptake was decreased in accumbic synaptosomes, but not significantly altered in striatal synaptosomes. Finally, STOP knockout mice were hypersensitive to acute and subchronic locomotor effects of cocaine, although the drug equally inhibited DA uptake in mutant and wild-type mice. Altogether, these data showed that deletion of the ubiquitous STOP protein elicited restricted alterations in DAergic neurotransmission, preferentially in the meso-limbic pathway.
Bouvrais-Veret
Caroline
C
Inserm, U513, Créteil, France, and Univ Paris 12, Faculté de Médecine Henri Mondor, Créteil, France.
Weiss
Stéphanie
S
Hanoun
Naima
N
Andrieux
Annie
A
Schweitzer
Annie
A
Job
Didier
D
Hamon
Michel
M
Giros
Bruno
B
Martres
Marie-Pascale
MP
D000704:Analysis of Variance; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency*; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D011859:Radiography; D011954:Receptors, Dopamine / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D008869:Microtubule-Associated Proteins; C491893:Mtap6 protein, mouse; D011954:Receptors, Dopamine; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine