Microtubule stabilizer ameliorates synaptic function and behavior in a mouse model for schizophrenia.
BACKGROUND
Recent data suggest that cytoskeletal defects may play a role in schizophrenia. We previously imitated features of schizophrenia in an animal model by disrupting gene coding for a microtubule-associated protein called STOP. STOP-null mice display synaptic defects in glutamatergic neurons, hyper-dopaminergy, and severe behavioral disorders. Synaptic and behavioral deficits are amended by neuroleptic treatment in STOP-null mice, providing an attractive model to test new antipsychotic agents. We examined the effects of a taxol-related microtubule stabilizer, epothilone D.


METHODS
Mice were treated either with vehicle alone or with epothilone D. Treatment effects on synaptic function were assessed using electron-microscopy quantification of synaptic vesicle pools and electrophysiology in the CA1 region of the hippocampus. Dopamine transmission was investigated using electrochemical assays. Behavior was principally assessed using tests of maternal skills.


RESULTS
In STOP-null mice, treatment with epothilone D increased synaptic vesicle pools, ameliorated both short- and long-term forms of synaptic plasticity in glutamatergic neurons, and had a dramatic beneficial effect on mouse behavior.


CONCLUSIONS
A microtubule stabilizer can have a beneficial effect on synaptic function and behavior, suggesting new possibilities for treatment of schizophrenia.
Andrieux
Annie
A
Laboratoire du Cytosquelette, INSERM U366 CEA, Département Réponse et Dynamique Cellulaire, Grenoble, France. annie.andrieux@cea.fr
Salin
Paul
P
Schweitzer
Annie
A
Bégou
Mélina
M
Pachoud
Bastien
B
Brun
Philippe
P
Gory-Fauré
Sylvie
S
Kujala
Pekka
P
Suaud-Chagny
Marie-Françoise
MF
Höfle
Gerhard
G
Job
Didier
D
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D034261:Epothilones / Q000008:administration & dosage*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000473:pathology; D008297:Male; D008425:Maternal Behavior / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D050257:Tubulin Modulators / Q000008:administration & dosage*
D034261:Epothilones; D008869:Microtubule-Associated Proteins; C491893:Mtap6 protein, mouse; D050257:Tubulin Modulators