Comorbidity between epilepsy and depression: experimental evidence for the involvement of serotonergic, glucocorticoid, and neuroinflammatory mechanisms

Abstract

Depression represents one of the most common comorbidities of temporal lobe epilepsy (TLE), and has profound negative impact on the quality of life of patients with TLE. However, causes and mechanisms of depression in TLE remain poorly understood, and effective therapies are lacking. We examined whether a commonly used model of TLE in rats could be used as a model of comorbidity between epilepsy and depression suitable for both mechanistic studies and for the development of mechanism-based antidepressant therapies. We established that animals that had been subjected to lithium chloride and pilocarpine status epilepticus (SE) and developed spontaneous recurrent seizures, exhibited a set of impairments congruent with a depressive state: behavioral equivalents of anhedonia and despair, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, and compromised raphe-hippocampal serotonergic transmission. Pharmacologic studies have suggested that depressive impairments following SE develop as a result of enhanced interleukin-1beta signaling in the hippocampus, which leads to depression via inducing perturbations in the HPA axis and subsequent deficit in the raphe-hippocampal serotonergic transmission.

Figure 1

Proposed mechanisms of depression as a comorbidity of temporal lobe epilepsy. Chronic epilepsy leads to the dysregulation of the HPA axis (Mazarati et al., 2009a) via several putative mechanisms, one of those being activation of IL-1β signaling in the hippocampus (Mazarati et al., 2009b). One of possible consequences of the dysregulation of the HPA axis is the upregulation of 5-HT1A somatodendritic receptors in dorsal raphe and subsequent increased autoinhibition of serotonin release in the raphe-hippocampal pathway. The latter has not been yet confirmed directly in the pilocarpine model, but is suggested by behavioral and biochemical experiments involving the administration of glucocorticoid and 5-HT1A blockers into the raphe of post-SE rats. The resulting compromised raphe-hippocampal serotonergic transmission (Mazarati et al. 2008) leads to behavioral symptoms of depression (Mazarati et al., 2008, 2009a,b).