Sustained Increase in Narp Protein Expression Following Repeated Electroconvulsive Seizure

Abstract

The delayed response to many psychiatric treatment regimens has focused attention on identifying enduring changes in gene expression following repeated stimulation that may contribute to these responses. Recent studies have identified Narp protein as a neuronal immediate early gene product that remains elevated in the hippocampus nearly 24 hours after a single episode of electroconvulsive seizure (ECS). To examine how Narp expression responds to repeated stimulation, we have examined the effect of repeated ECS on Narp expression in the hippocampusA central focus of current research in psychopharmacology is to understand the molecular alterations that underlie the long-term effects of psychiatric treatments. Accordingly, there has been intense interest in identifying slowly developing or prolonged changes in gene expression that are induced by repeated administration of psychotropic drugs or ECT (Hyman and Nestler 1996). Although a single ECS episode triggers a rapid induction of multiple immediate early genes (IEG), in most cases examined to date, the expression of these IEGs follows a rapid and transient time course making it unclear whether they contribute to long-term changes elicited by these treatments. Two notable exceptions to this pattern are ⌬ Fos B (Chen et al. 1997;Hiroi et al. 1998) and BDNF (Duman andNibuya et al. 1995;Zetterstrom et al. 1998), which display enduring changes in expression following chronic treatment regimens.In recent studies, Narp has been identified as an IEG product that also displays an atypical, sluggish time course of expression, as it takes 4-8 hours to reach peak levels and remains elevated for nearly 24 hours after a single ECS (O'Brien et al. 1999;Tsui et al. 1996). Functional analysis of Narp has provided compelling evidence that it regulates clustering of AMPA receptors at synaptic sites and may therefore contribute to alterations in excitatory synaptic transmission induced by neuronal stimulation. Both the distinctive time course displayed by Narp and its link to synaptic plasticity make it an attractive candidate gene that might mediate long-term effects of psychiatric treatments. Accordingly, as an initial step in examining how its expression is affected by repeated stimulation, we have monitored the expression of Narp protein following repeated ECS. MATERIALS AND METHODSMaximal ECS was administered to male Sprague-Dawley rats (175-200 g) (Harlan, Indianapolis, IN) as described in Cole et al. (1990). Sham treated rats were handled identically to those receiving ECS except for administration of the electrical current. For repeated ECS, stimulation was administered at 48 hour intervals.To monitor Narp protein levels at various times after single or repeated ECS, animals were killed by decapitation with a small animal guillotine. Hippocampal tissues were dissected and then placed in Laemmli sample buffer (BioRad, Hercules, CA) with additional SDS (3% final concentration). Samples were homogenized, then heated for 1 minute at 65 Њ C. Except where explicitly stated, highe...

Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission

“…16,17 A series of spaced ECS treatments was also shown to enhance the expression of Narp protein, an immediate early gene product that probably plays a regulatory role in the clustering of AMPA receptors at synaptic sites. 30 Although the expression of mRNA for the NR1 subunit was unchanged in our study, 28 ECS treatment has been shown to alter the expression of mRNA for other NMDA receptor subunits. Watkins et al 31 found that chronic ECS treatment produced an acute increase in mRNA for both the NR2A and NR2B subunits of the NMDA receptor in the dentate gyrus, although only the NR2B increase was sustained 24 h later.…”

Opiate Withdrawal Induces Narp in the Extended Amygdala

“…In previous studies, we have demonstrated that this antibody is highly specific for Narp, as assessed by immunobloting of brain extracts and immunohistochemistry (Reti and Baraban, 2000;Reti et al, 2002a, b, c). Other primary antibodies used for immunohistochemistry were: rabbit polyclonal Arc (1 : 500; Lyford et al, 1995) and goat polyclonal c-Fos (1 : 100; Santa Cruz).…”

“…As a control for Arc immunostaining in the amygdala, one animal also received electroconvulsive shock (as described in Reti and Baraban, 2000) and was killed 4 h later for processing of hippocampal sections.…”

St John's wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response

“…Specific effects of antidepressants or electroconvulsive treatment have already been reported for immediate early genes and transcription factors such as c-fos, zif268, NGF1-A, phosphorylation of CRE-binding protein, DfosB, and Narp. [65][66][67][68][69][70][71][72] In our analysis, we identified four genes that were downregulated in response to both IMI and SJW. Such genes could be potential markers for predicting response to antidepressant treatment; however, the fact that genes are coordinately downregulated suggests there are specific combinations of transcriptional regulators that control the expression of these four genes.…”