Differential regulation of synaptic vesicle proteins by antidepressant drugs

Abstract

Synaptic vesicle proteins (SVP) play a critical role in neurotransmitter release and neural plasticity, and have been implicated in the pathophysiology of psychiatric disorders such as depression. Antidepressant drugs not only alter the level of neurotransmitters, but also modulate de novo gene transcription and synthesis of proteins involved in neural plasticity. In order to investigate the effects of antidepressant compounds on SVP-mRNA levels, the expressions of synaptophysin, synaptotagmin, VAMP, and synapsin-I were analysed by in situ hybridization in rats which had been treated with desipramine, fluoxetine, tranylcypromine, or saline. The results demonstrate that chronic treatment with fluoxetine and tranylcypromine leads to an increased expression of synaptophysin, but decreased expression of synaptotagmin and VAMP in the hippocampus and cerebral cortex. Additionally, synapsin ImRNA levels in the hippocampus and cerebral cortex are significantly reduced in tranylcypromine-treated animals. This identifies SVP genes as target genes of antidepressant treatment. Keywords: depression; psychopharmacology; psychosis; SSRI; synapsin; synaptophysin INTRODUCTION Synaptic vesicle proteins (SVP) such as synapsin I-III, synaptophysin, synaptotagmin, and synaptobrevin (VAMP -vesicle-associated membrane protein) play a critical role in synaptic plasticity, and are required for vesicle fusion and neurotransmitter release. [1][2][3][4][5][6] Hence, changes in the expression of these proteins may contribute to the molecular effects of antidepressant treatment and associated behavioral and cognitive alterations. Previous studies have shown that antidepressants modulate de novo gene transcription and synthesis of proteins involved in neural and synaptic plasticity; in a recent transcriptomic study, a decreased expression of VAMP was found with imipramine and sertraline. 7 In order to investigate the effects of antidepressant compounds on synaptic plasticity, the expression of SVP was analysed by in situ hybridization in rats which had been treated with desipramine, fluoxetine, tranylcypromine, or saline (control group) for 2 weeks.

Mifepristone Repairs Region-Dependent Alteration of Synapsin I in Hippocampus in Rat Model of Depression

“…The effects of mifepristone on the mRNA level of synapsin I are not quite the same as tranylcypromine. Mifepristone decreases synapsin I in DG/CA3 and increases it in CA1 subfield in hippocampus, whereas tranylcypromine decreases synapsin I in both DG/ CA3 and CA1 subfields (Rapp et al, 2004). This difference may be explained by using different animal models.…”

“…There are a few reports about the effects of antidepressants on synapsin I in rat hippocampus. Chronic treatment with tranylcypromine, but not desipramine or fluoxetine, decreases synapsin I mRNA expression in rat hippocampal DG, CA3, and CA1 (Rapp et al, 2004), and imipramine or fluvoxamine decreases synapsin I immunoreactivity in rat hippocampus (Iwata et al, 2006). Another study showed that injecting rats with lithium for 30 days produces no changes in total synapsin in the hippocampus (Vawter et al, 2002).…”

“…Contrasted with the normal unhandled rats used in the study of Rapp et al (2004), the rat model of depression induced by chronic stress was used in the studies of Krugers et al (2006) and in our own study. Considering EEAs in DG/ CA3 is a major risk factor for the hippocampal atrophy induced by chronic stress (Watanabe et al, 1992;Magarinos et al, 1996), the selective inhibition of synapsin I by mifepristone may have a unique advantage compared with the general inhibition of synapsin I in both DG/CA3 and CA1, as shown by a classic antidepressant such as tranylcypromine.…”

Chronic Fluoxetine Treatment Increases the Expression of PSA-NCAM in the Medial Prefrontal Cortex

“…As chronic stress also induces dendritic atrophy and spine loss in mPFC pyramidal neurons (Radley et al, 2004;Wellman, 2001), it is feasible that fluoxetine treatment may induce the opposite effect. The fact that chronic fluoxetine treatment induces an increase in synaptohysin (a protein specific of synapses) expression in the cerebral cortex (Rapp et al, 2004), gives support to this hypothesis. However, studies on the structure of mPFC neurons after antidepressant treatment should be performed to clarify this matter.…”

Long-Term Adaptive Changes Induced by Antidepressants: From Conventional to Novel Therapies

“…Interestingly, chronic exposure to second-generation antispychotics olanzapine or risperidone enhances PSA-NCAM expression in the PFC, but not in the hippocampus, suggesting that modulation of cell adhesion protein in the hippocampus may be specific to the mechanism of action of ADs [152,153]. Moreover, an increased expression of synaptophysin, a glycoprotein localized in presynaptic vesicle membranes required for docking and fusion of neurotransmitter-containing synaptic vesicles as well as endocytosis [154], was observed in hippocampus and/or cerebral cortex of rats chronically treated with the MAOI tranylcypromine, the TCA amitriptyline or the SSRI fluoxetine [148,155,156]. Also, Arc (Activity-regulated, cytoskeletalassociated protein), a highly expressed protein in dendrites and postsynaptic densities [157] is implicated in LTP and spine size and type [158][159][160].…”