Clozapine regulation of p90RSK and c-Fos signaling via the ErbB1-ERK pathway is distinct from olanzapine and haloperidol in mouse cortex and striatum

Treatment of the positive psychotic symptoms of schizophrenia with standard antipsychotic drugs (APDs) is ineffective in a proportion of cases. For these treatment resistant patients the alternative is the APD clozapine which is superior to other agents but carries serious side effects. Why clozapine is uniquely effective is unknown, but we have previously postulated may involve G-protein coupled receptor (GPCR) and epidermal growth factor (EGF) receptor (ErbB1) transactivation signaling to the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade. This was based upon clozapine induced initial down-regulation and delayed ErbB1 mediated activation of the cortical and striatal ERK response in vivo distinct from other APDs. This study investigated if modulation of the ErbB1-ERK1/2 pathway by clozapine, olanzapine and haloperidol affected expression of the ERK substrates p90RSK and c-Fos, factors that regulate transcription of proteins associated with neuroplasticity and synapse formation in C57Bl/6 mice. In cortex and striatum, acute clozapine treatment induced biphasic p90RSK phosphorylation via MEK that paralleled ERK phosphorylation independent of EGF receptor blockade. By contrast, olanzapine and haloperidol caused p90RSK phosphorylation that was not concomitant with ERK signaling over a 24-hour period. For c-Fos, clozapine elevated expression 24 h after administration, a timeframe consistent with ERK activation at 8 h. Alternatively, haloperidol stimulation of c-Fos levels limited to the striatum was in accord with direct transcriptional regulation through ERK. The unique spatio-temporal expression of downstream nuclear markers of the ErbB1-ERK pathway invoked by clozapine may contribute to its effectiveness in treatment resistant schizophrenia.

► Antipsychotic drugs differentially target the ERK substrates p90RSK and c-Fos. ► Clozapine induces biphasic p90RSK phosphorylation that mimics ERK phosphorylation. ► Olanzapine and haloperidol phosphorylate p90RSK discordant with ERK signaling. ► Elevation of c-Fos by clozapine is consistent with timeframe of ERK activation. ► Spatio-temporal effect of clozapine on p90RSK/c-Fos may contribute to efficacy in treatment resistant schizophrenia.