Regulation of biochemical and electrical signaling in mouse prefrontal cortex by clozapine, a therapeutic agent for schizophrenia.
Item
-
Title
-
Regulation of biochemical and electrical signaling in mouse prefrontal cortex by clozapine, a therapeutic agent for schizophrenia.
-
Identifier
-
AAI3325380
-
identifier
-
3325380
-
Creator
-
Kanjilal, Baishali.
-
Contributor
-
Adviser: Probal Banerjee
-
Date
-
2008
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Biology, Neuroscience
-
Abstract
-
Atypical antipsychotic-induced cortical dopamine release, which is believed to improve the negative and cognitive symptoms of Schizophrenia, is reportedly mediated by 5HT2A/D2 receptor blockade and activation of 5HT1A receptor (5-HT1A-R) in rat prefrontal cortex (PFC). In the present study we have investigated the involvement of the 5-HT1A receptor in clozapine-evoked regulation of electrical signals in PFC slices. Clozapine (15 muM) showed a dramatic increase in population spike in PFC slices isolated from postnatal (Day-20-30) mouse brain. This increase in neuronal activity was eliminated in the presence of the 5-HT 1A receptor antagonist WAY100635, the phospholipase C (PLC) inhibitor U73122, and a membrane permeable Ca2+/CaM Kinase IIalpha (CaMKIIalpha) inhibitor. In contrast, the MAP kinase kinase (MEK) inhibitor PD98059 failed to block the effect. Clozapine therefore functions as a 5-HT 1A-receptor agonist, and PLC and CaMKIIalpha are also involved in the clozapine-evoked signaling that results in an increase in electrical activity in the PFC. As revealed by Western blot analysis for CaMKIIalpha phosphorylation at T286, 15 min of clozapine treatment of PFC slices evokes maximal activation of CaMKIIalpha and this induction is completely blocked by WAY100635. Thus, our observations from electrical as well as biochemical analyses suggest that clozapine elicits induced electrical activity in the PFC through a 5-HT1A-R-mediated signaling pathway that involves CaMKIIalpha. The involvement of the 5-HT1A-R was further corroborated by a dramatic increase in electrical activity and CaMKIIalpha activation following treatment with the 5-HT1A-R agonist 8-OH-DPAT. Clozapine also showed a significant increase in population spike in 5-HT1A-R(-/-) mice. However, a CaMKII inhibitor failed to block the effect of clozapine in knockout mice, indicating the involvement of other receptors that do not require CaMKII activation. The clozapine-induced electrical activity in the PFC also involved the NMDA receptor because it was completely eliminated upon pretreatment of the slices with the NMDA antagonist APV. Collectively, our findings indicate a synergism between the NMDA receptor and 5-HT1A-R-mediated signaling via CaMKIIalpha, which is responsible for PFC activity elicited by the antipsychotic agent clozapine.
-
Type
-
dissertation
-
Source
-
PQT Legacy CUNY.xlsx
-
degree
-
Ph.D.
