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, byper-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 CA 1 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.