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.
Key Words
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Article info
Publication history
Published online: June 28, 2006
Accepted:
March 14,
2006
Received in revised form:
March 13,
2006
Received:
October 12,
2005
Identification
Copyright
© 2006 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
