NDLI: Clozapine-Induced ERK1 and ERK2 Signaling in Prefrontal Cortex Is Mediated by the EGF Receptor

Content Provider	Springer Nature Link
Author	Pereira, Avril Fink, George Sundram, Suresh
Copyright Year	2009
Abstract	The atypical antipsychotic drug clozapine is effective in treatment-refractory schizophrenia. The intracellular signaling pathways that mediate clozapine action remain unknown. A potential candidate is the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) cascade that links G-protein-coupled receptor and ErbB growth factor signaling systems, thereby regulating synaptic plasticity and connectivity, processes impaired in schizophrenia. Here, we examined how clozapine differentially modulated phosphorylation of the MAPK isoforms, ERK1/ERK2 in primary murine prefrontal cortical neurons compared to the typical antipsychotic drug haloperidol. While clozapine and haloperidol acutely decreased cortical pERK1 activation, only clozapine but not haloperidol stimulated pERK1 and pERK2 with continued drug exposure. This delayed ERK increase however, did not occur via the canonical dopamine D$_{2}$-Gi/o-PKA or serotonin 5HT$_{2A}$-Gq-phospholipase-C-linked signaling pathways. Rather, epidermal growth factor (EGF) receptor signaling mediated clozapine-induced ERK activation, given dose-dependent reduction of pERK1 and pERK2 stimulation with the EGF receptor inhibitor, AG1478. Immunocytochemical studies indicated that clozapine treatment increased EGF receptor (Tyr1068) phosphorylation. In vivo mouse treatment studies supported the in vitro findings with initial blockade, subsequent activation, and normalization of the cortical ERK response over 24 h. Furthermore, in vivo clozapine-induced ERK activation was significantly reduced by AG1478. This is the first report that clozapine action on prefrontal cortical neurons involves the EGF signaling system. Since EGF receptor signaling has not been previously linked to antipsychotic drug action, our findings may implicate the EGF system as a molecular substrate in treatment-resistant schizophrenia.
Starting Page	185
Ending Page	198
Page Count	14
File Format	PDF
ISSN	08958696
Journal	Journal of Molecular Neuroscience
Volume Number	39
Issue Number	1-2
e-ISSN	15591166
Language	English
Publisher	Humana Press Inc
Publisher Date	2009-03-10
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Antipsychotic drug Schizophrenia ERK EGF receptor Prefrontal cortex Signal transduction Neurology Neurosciences
Content Type	Text
Resource Type	Article
Subject	Medicine Cellular and Molecular Neuroscience

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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