Antidepressants differentially affect expression of complexin I and II RNA in rat hippocampus

Abstract

Disturbance of synaptic transmission is currently viewed as an important pathophysiological mechanism and therapeutic target of mood disorders. Amongst other lines of evidence this theory is based on human post-mortem investigations showing differential expression of complexins. In order to discriminate between molecular correlates of the disease itself and effects of psychotropic drugs given to patients, we performed an animal trial using subchronic antidepressant treatment. Cohorts of adult male Sprague-Dawley rats were treated over a period of 14 days with intraperitoneal injections of either saline (0.9%, n=8), desipramine (15 mg/kg, n=7), fluoxetine (10 mg/kg, n=8), or tranylcypromine (10 mg/kg, n=5). Brain slices were used for in situ hybridizations with 35S labelled RNA probes of the genes complexin I, complexin II and syntaxin 1 A, the SNARE complex protein interacting with the complexins, and assessed semi-quantitatively for region-specific expression levels. Expression of complexin I was induced only in habenular nuclei after treatment with fluoxetine. In contrast, complexin II was significantly induced by desipramine and tranylcypromine, but not fluoxetine, in several brain regions. All treatment groups, but most significantly fluoxetine-treated animals, showed higher expression levels of syntaxin 1A. Antidepressants differentially affect expression levels of complexin I and more prominently complexin II and syntaxin 1A. The induction of complexin II and syntaxin 1A might strengthen the synaptic transmission at axo-dendritic or axo-axonal synapses. Previous post-mortem findings reporting on downregulation of complexins cannot be explained as mere effects of psychotropic drug treatment.

Reduced Expression of GABA Transporter GAT3 in Helpless Rats, an Animal Model of Depression

“…in the hippocampal formation, the habenula, the cerebral cortex, the amygdala and thalamic subregions. Previous results on altered expression of synaptic vesicle proteins after antidepressive treatment and in this model [57,65,72] as well as altered glutamatergic parameters in the LH-model (Zink et al submitted) should be integrated in a network-based view of the dysregulations in helplessness and depression. This comprehensive view might help to establish a link between changes of synaptic gene expression, the GABAergic and glutamatergic system and functional alterations of brain metabolism, in particular with regard to functional deficits of glial cells.…”

“…In situ hybridizations [65] were performed on two sections of each animal (n = 6 per cohort) with 35 S-UTPlabelled cRNA-probes of GAD 67 , VGAT, GAT1 and GAT3 as listed in Table 2. The sequence similarity of the probe for GAD 67 , the major synthesising enzyme of GABA [12], with GAD 65 is 72% with no extended stretches of identical parts.…”

“…The amino acid neurotransmitter GABA is synthesised by glutamic acid decarboxylase (GAD), which occurs in two molecular forms, GAD 65 and GAD 67 , while the lastmentioned enzyme synthesises the majority of GABA [12]. GABA transporter genes (GAT) have been cloned and functionally characterised in a number of species including humans and rats [13][14][15].…”

Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment

“…More traditional behavioral tests such as learned helplessness or the forced swim test are responsive to acute or subchronic administration of antidepressants (Cryan et al, 2002), and are not as suitable for studies of neurogenesis. It is possible that antidepressants influence behavior in these models by regulation of synaptic function of newborn, as well as mature neurons, a possibility supported by recent studies demonstrating antidepressant regulation of synaptic signaling proteins and spine formation in the hippocampus (Hajszan et al, 2005;Zinc et al, 2005).…”

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

“…In situ hybridizations (Zink et al 2005) were performed on two individual sections of each animal (n=6 per group) with 35 S-UTP-labeled cRNA probes of the genes listed in Table 2. The cDNA sequences were selected for sufficient specificity between closely related genes, cloned into vectors with direction-specific primers for the initiation of in vitro transcription, and checked by commercial sequencing.…”