The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders.
Neurons contain abundant subsets of highly stable microtubules that resist depolymerizing conditions such as exposure to the cold. Stable microtubules are thought to be essential for neuronal development, maintenance, and function. Previous work has indicated an important role of the microtubule-associated protein STOP in the induction of microtubule cold stability. Here, we developed STOP null mice. These mice were devoid of cold-stable microtubules. In contrast to our expectations, STOP-/- mice had no detectable defects in brain anatomy but showed synaptic defects, with depleted synaptic vesicle pools and impaired synaptic plasticity, associated with severe behavioral disorders. A survey of the effects of psychotropic drugs on STOP-/- mice behavior showed a remarkable and specific effect of long-term administration of neuroleptics in alleviating these disorders. This study demonstrates that STOP is a major factor responsible for the intriguing stability properties of neuronal microtubules and is important for synaptic plasticity. Additionally, STOP-/- mice may yield a pertinent model for study of neuroleptics in illnesses such as schizophrenia, currently thought to result from synaptic defects.
Andrieux
Annie
A
Laboratoire du Cytosquelette, INSERM U366, Département Réponse et Dynamique Cellulaire, CEA-Grenoble, 38054 Grenoble, France.
Salin
Paul A
PA
Vernet
Muriel
M
Kujala
Pekka
P
Baratier
Julie
J
Gory-Fauré
Sylvie
S
Bosc
Christophe
C
Pointu
Hervé
H
Proietto
Dominique
D
Schweitzer
Annie
A
Denarier
Eric
E
Klumperman
Judith
J
Job
Didier
D
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D003080:Cold Temperature; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008870:Microtubules / Q000473:pathology / Q000502:physiology; D009473:Neuronal Plasticity; D013569:Synapses / Q000473:pathology / Q000502:physiology*; D009435:Synaptic Transmission
D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; C491894:MAP6 protein, human; D008869:Microtubule-Associated Proteins; C491893:Mtap6 protein, mouse