Glycogen synthase kinase-3β heterozygote knockout mice as a model of findings in postmortem schizophrenia brain or as a model of behaviors mimicking lithium action: negative results

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In mice glycogen synthase kinase (GSK)-3β heterozygote knockout status was reported to cause reduced immobility in the Porsolt forced swim test and reduced amphetamine-induced hyperactivity, behaviors that mimic the effects of lithium. GSK-3β protein and mRNA level and activity have been reported to be reduced in the postmortem brain of schizophrenia patients and this could suggest the involvement of GSK-3β in the etiology of schizophrenia. However, apomorphine-induced stereotyping was reported to be unchanged in GSK-3β heterozygote (HZ) knockout (KO) mice. As such behaviors are not always robust, study in another laboratory seemed indicated. Motor activity and coordination were assessed in the rotarod test. Behavior was studied in the following tests: pilocarpine-induced seizures model for lithium action, Porsolt forced swim test, tail suspension test, elevated plus-maze, large open field, startle response and prepulse inhibition of acoustic startle response, amphetamine-induced hyperactivity, and apomorphine-induced stereotypic climbing. We could not confirm the report that GSK-3β HZ KO mice exhibit reduced immobility in the Porsolt forced swim or reduced amphetamine-induced hyperactivity in a manner mimicking the behavioral effects of lithium. We did not find increased apomorphine-induced stereotypic climbing or disruption of prepulse inhibition, suggesting that human postmortem findings regarding GSK-3β in schizophrenia are not mediated by changes in dopamine receptors and are not the cause of prepulse inhibition deficits in schizophrenia. These data do not support the role of GSK-3β in schizophrenia or in the mechanism of therapeutic action of lithium. Although differences in the genetic background of the GSK-3β HZ KOs used in the present study compared with that of the previous study could be responsible, such results could suggest that the previously reported effects of GSK-3β knockout on behavior are not robust.

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