Glial cell activation in response to electroconvulsive seizures

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Abstract

Electroconvulsive therapy (ECT) is a very efficient treatment for severe depression. However, cognitive side effects have raised concern to whether ECT can cause cellular damage in vulnerable brain regions. A few recent animal studies have reported limited hippocampal cell loss, while a number of other studies have failed to find any signs of cellular damage and some even report that electroconvulsive seizures (ECS; the animal counterpart of ECT) has neuroprotective effects.

We previously have described gliogenesis in response to ECS. Loss of glial cells is seen in depression and de novo formation of glial cells may thus have an important therapeutic role. Glial cell proliferation and activation is however also seen in response to neuronal damage. The aim of the present study was to further characterize glial cell activation in response to ECS.

Two groups of rats were treated with 10 ECS using different sets of stimulus parameters. ECS-induced changes in the morphology and expression of markers typical for reactive microglia, astrocytes and NG2+ glial cells were analyzed immunohistochemically in prefrontal cortex, hippocampus, amygdala, hypothalamus, piriform cortex and entorhinal cortex. We observed changes in glial cell morphology and an enhanced expression of activation markers 2 h following ECS treatment, regardless of the stimulus parameters used. Four weeks later, few activated glial cells persisted.

In conclusion, ECS treatment induced transient glial cell activation in several brain areas. Whether similar processes play a role in the therapeutic effect of clinically administered ECT or contribute to its side effects will require further investigations.

Introduction

Electroconvulsive therapy (ECT) is one of the most efficient antidepressant treatments available (Weiner et al., 2001). The main indication for ECT is major depression with vegetative symptoms (melancholia) where outstanding remission rates are achieved (Abrams, 2002). Several other conditions, for instance catatonia and severe manic states, respond well to ECT (Weiner et al., 2001). Since the introduction in 1938 the procedure has been refined several times. Modern ECT is given under full anesthesia, with muscle relaxation and preoxygenation. Electrode placement and stimulus parameters (frequency, pulse width, electrical current, and stimulus duration) have also been modified in an attempt to minimize cognitive side effects (Loo et al., 2006). Despite this, memory disturbances are seen in many patients (Sackeim et al., 2007), and even if these side effects in the majority of cases are mild and transient, further improvements are sought for.

The principle of ECT is the induction of a brief (approximately 30 s) generalized grand mal seizure. It is well known that seizures of long duration, for example status epilepticus (defined as ongoing cerebral seizures for more than 30 min), are associated with cell death in certain brain regions (Fujikawa, 2005). It is therefore a reasonable assumption that some cell death also might occur after seizures of short duration, i.e. ECT. Results from research on electroconvulsive stimulation (ECS), the animal counterpart of ECT, is however inconclusive, with reports of both neuronal cell death and neuroprotective effects. Diverging ECS treatment techniques within preclinical research might be a possible explanation for the discrepancy in results.

Neuronal damage or death is followed by activation of glial cells, a process often referred to as ‘reactive gliosis’. All glial cell types other than oligodendrocytes, i.e. microglia, astrocytes and chondroitin sulphate proteoglycan NG2 expressing glial cells (NG2+ cells), respond to brain damage by cell division, morphological changes and by assuming novel capabilities (Butt et al., 2002, Hampton et al., 2004). We have previously shown that ECS enhances the proliferation of microglia and NG2+ cells in the hippocampus and amygdala of adult rats (Wennstrom et al., 2003, Wennstrom et al., 2004). Others have reported an increased glial cell proliferation in the prefrontal cortex (Madsen et al., 2005) as well as morphological alterations of hippocampal microglia, in response to ECS (Jinno and Kosaka, 2008). No increase in astrocyte proliferation following ECS was detected in our previous studies (Wennstrom et al., 2003, Wennstrom et al., 2004), but others have described an ECS-induced activation of astrocytes, seen as an upregulation of glial fibrillary acidic protein (GFAP) (Dwork et al., 2004).

Oligodendrocytes (to which NG2-cells are precursors), microglia and astrocytes have all been suggested to be implicated in the pathophysiology of depression (Banasr and Duman, 2007, McNally et al., 2008, Rajkowska and Miguel-Hidalgo, 2007). Whether the stimulatory effect of ECS on glial cell plasticity contributes to the therapeutic effects or is indicative of cell damage is not known. Overall, little is known about the nature of the glial cell response to ECS. The aim of this study was to further investigate the glial cell response to ECS, comparing two different sets of stimulus parameters.

Section snippets

Animals and study design

Adult male Wistar rats (Harlan Laboratories, Holland), weighing 200 g at the beginning of the experiments, were used. Experimental procedures were carried out according to the guidelines set by the Malmö/Lund ethical committee for the use and care of laboratory animals.

First, a pilot study was conducted to investigate the time course of the glial activation. ECS were given once daily for 10 days and rats were allowed to survive for 2 h, 2 days, 8 days and 20 days after the last ECS treatment.

Seizure duration

Repeated-measures ANOVA revealed that there was a slight increase in tonic seizure duration over time (F9.38 = 17.634; p < 0.0001). However, no significant difference between the ECS groups (F1.38 = 1.502; p = 0.2280) or interaction between group and time (F9.38 = 1.241; p = 0.2690) was found (Fig. 1).

Altered glial cell morphology in response to ECS

In sham-treated animals, Iba-1+ cells (microglia), GFAP+ cells (astrocytes) and NG2+ cells displayed morphologies typical of resting glial cells with slender processes (Fig. 2a–f). Two hours after ECS the

Discussion

The aim of this study was to investigate glial cell activation in response to ECS treatment. We observed alterations in the morphology of microglia, NG2+ glial cells and astrocytes in response to ECS, with the most significant changes found in hippocampus and piriform cortex. Furthermore, ECS treatment induced expression of the antigen-presenting molecule MHC II in microglia, particularly pronounced in the hippocampus. The lysosomal protein ED1 (expressed by phagocytic cells) was also

Conclusions

This study shows that ECS treatment causes glial cell activation in several limbic regions, characterized by morphological changes and the appearance of subpopulations of astrocytes expressing nestin, and microglia positive for MHC II and ED1. Although ECSL and ECSS generated slightly different results, the overall picture was that the two sets of stimulus parameters gave rise to similar responses. We believe that studies on glial cell activation in response to antidepressant treatment

Acknowledgements

This work was supported by the Swedish Research Council, the Segerfalk Foundation, the Swedish Lundbeck Foundation, the Sjöbring Foundation, the Anders Otto Swärd Foundation, the Royal Physiografic Society in Lund, the Organon Foundation and the Bror Gadelius Foundation.

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