Differential Expression of Synaptic Vesicle Proteins After Repeated Electroconvulsive Seizures in Rat Frontal Cortex and Hippocampus BETINA ELFVING,* BIRGIT EGESKOV BONEFELD, RABEN ROSENBERG, AND GREGERS WEGENER Centre for Psychiatric Research, Aarhus University Hospital, Risskov, DK-8240 Risskov, Denmark KEY WORDS rat brain; qPCR; acute ECS; repeated ECS; synaptic vesicle proteins ABSTRACT Electroconvulsive therapy (ECT) remains the treatment of choice for patients with severe or drug-resistant depressive disorders, yet the mechanism behind its efficacy and the effect on neurotransmission is essentially unknown. As synaptic vesicle proteins (SVPs) are required for vesicle fusion and neurotransmitter release, we have examined the effect of single and repeated electroconvulsive seizures (ECS), an animal model of ECT, on the expression of 14 SVPs in the rat frontal cortex and the hippocampus using quantitative real-time polymerase chain reaction (real-time qPCR). Only in the frontal cortex, the mRNA level of synapsin II was significantly upregulated after repeated ECS. In contrast, the mRNA levels of 6 of the 14 SVPs were significantly regulated in the hippocampus after ECS. We found that SNAP29 was upregulated and synaptotagmin III was downregulated after one single ECS in the hippocampus. Furthermore, SNAP29, synapsin I, synapsin III, VAMP2, and VAMP5 were significantly upregulated, whereas synaptotagmin III was significantly downregulated after repeated ECS in the hippocampus. We suggest that these genes are highly important in the long-term therapeutic effect of ECS, and thus it can be hypothesized that the SVPs are involved in the pathophysiology of depression. Synapse 62:662–670, 2008. V V C 2008 Wiley-Liss, Inc. INTRODUCTION Current depression treatment includes various forms of pharmacotherapy with both antidepressants and psychotherapy. In severe cases or in treatment- resistant depression, electroconvulsive therapy (ECT) is applied. In Denmark, 18% of the depressed inpa- tients are given ECT (Andersson and Bolwig, 2002). ECT is the most powerful treatment of severe mel- ancholic/psychotic depression. Among cases with major depression, the efficacy of ECT is between 85 and 90%, whereas the efficacy of antidepressant ther- apy is only 60–65% (Schloss and Henn, 2004). There- fore, identification of some of the molecular and cellu- lar mechanisms affected by ECT may provide further insight into the pathophysiology of depression and help optimize the treatment regimens. Recent studies have suggested that electroconvulsive seizures (ECS), an animal model of ECT, causes a number of cellular changes, such as increased neurogenesis, increased cell proliferation, mossy fiber sprouting, and an enhanced synaptic response (Burnham et al., 1995; Gombos et al., 1999; Lamont et al., 2001; Madsen et al., 2000, 2005; Stewart et al., 1994; Vaidya et al., 1999). Accordingly, molecular changes have also been reported as ECS regulates gene expression of distinct neurotrophic signaling pathways (Altar et al., 2004) and causes a widespread release of neurotrans- mitters, which affects a variety of transporters and receptors in the brain (Schloss and Henn, 2004). Despite the fact that ECS affects neurotransmitter release, only few studies investigating the involve- ment of synaptic vesicle proteins (SVPs) in the mech- anism of action of ECS have been conducted. Contract grant sponsors: Danish Research Agency, Ministry of Science, Tech- nology and Innovation, Augustinus Foundation, Sawmill Owner Jeppe Juhl, Ovita Juhl Memorial Foundation *Correspondence to: Betina Elfving, Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, DK-8240 Risskov, Denmark. E-mail: bef@psykiatri.aaa.dk Received 13 December 2007; Accepted 26 February 2008 DOI 10.1002/syn.20538 Published online in Wiley InterScience (www.interscience.wiley. com). V V C 2008 WILEY-LISS, INC. SYNAPSE 62:662–670 (2008)