Abstract
Olfactory Bulbectomy Leads to the Development of Epilepsy in Mice.
Jiang Y, Pun RY, Peariso K, Holland KD, Lian Q, Danzer SC. PLoS One 2015;10:e0138178.
There is a clear link between epilepsy and depression. Clinical data demonstrate a 30–35% lifetime prevalence of depression in patients with epilepsy, and patients diagnosed with depression have a three to sevenfold higher risk of developing epilepsy. Traditional epilepsy models partially replicate the clinical observations, with the demonstration of depressive traits in epileptic animals. Studies assessing pro-epileptogenic changes in models of depression, however, are more limited. Here, we examined whether a traditional rodent depression model—bilateral olfactory bulbectomy—predisposes the animals towards the development of epilepsy. Past studies have demonstrated increased neuronal excitability after bulbectomy, but continuous seizure monitoring had not been conducted. For the present study, we monitored control and bulbectomized animals by video-EEG 24/7 for approximately two weeks following the surgery to determine whether they develop spontaneous seizures. All seven bulbectomized mice exhibited seizures during the monitoring period. Seizures began about one week after surgery, and occurred in clusters with severity increasing over the monitoring period. These results suggest that olfactory bulbectomy could be a useful model of TBI-induced epilepsy, with advantages of relatively rapid seizure onset and a high number of individuals developing the disease. The model may also be useful for investigating the mechanisms underlying the bidirectional relationship between epilepsy and depression.
Commentary
A major co-morbidity between epilepsy and depression has been well established. Although most of the focus has been placed on the development of depression in people with epilepsy (1), clinical data also indicate that people with major endogenous depression have an increased risk of developing epilepsy (2). The circuit and cellular changes that could underlie the progression of epileptogenesis in relation to the pathophysiology of depression remain unclear. Critical tools that could facilitate understanding of the mechanisms driving depression-associated epilepsy include the development and characterization of animal models that exhibit behavioral correlates of depression, as well as seizures and epilepsy.
One animal model that has long been used in the study of depression is bilateral olfactory bulbectomy in rodents. In this procedure, the olfactory bulb tissue is removed by gentle suction. This can also lead to damage to the anterior olfactory nuclei, endopiriform nuclei, and piriform cortex. Rats and mice subjected to olfactory bulbectomy display increased rates of depressive-like behaviors, including hyperactivity, immobility in the forced swim test, and reduced sexual behaviors. In the present study, Jiang and colleagues used 24-hour continuous video/EEG recordings of mice to assess the potential for epileptogenesis and incidence of spontaneous recurrent seizures in this model.
All bulbectomized mice developed spontaneous seizures within 5 to 13 days after surgery. Regarding the high rate of development of epilepsy documented in this study, it is perhaps somewhat surprising that the presence of spontaneous recurrent seizures was not described previously, given the widespread use of this model in studying depression. The lack of detection may be explained by the finding that the seizures occurred in clusters and their presence could easily be missed if animals were not watched at the “right” time. In mice in which two seizure clusters were detected, the duration and severity of seizures was increased in the second cluster compared to the first. This finding suggests that the severity of epilepsy can increase over time in this model, although it should be noted that, in this study, EEG recordings were performed only for the relatively short period of approximately 2 weeks following the surgery.
Many forms of cortical trauma can lead to the development of epilepsy. In several of the mice treated in this study, there was some frontal cortical damage. Importantly, however, loss of cortical volume did not correlate with seizure frequency. In addition, no gross morphological changes were observed in the hippocampus. Although subtler histological and functional changes were not assessed here, this finding suggests that loss of olfactory input—even in absence of cortical damage—can result in functional epileptogenic alterations. One area that may be particularly critical to the development of epilepsy in this model is the piriform cortex. Epilepsy can result from kindling of the piriform cortex in animal models (3), and the piriform cortex has been implicated in human focal epilepsy (4).
Interestingly, one commonly observed consequence of olfactory bulbectomy in rats is a rise in circulating levels of the stress hormone corticosterone (5), which may result from hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis. HPA axis dysfunction has been implicated in both depression and epilepsy (6, 7), suggesting that this model of olfactory bulbectomy-induced epilepsy could also be useful in understanding the role of the stress response in this co-morbidity. Furthermore, women with epilepsy show an increased rate of depressive symptoms compared to men with epilepsy (8). In this study, no difference between male and female mice was observed, but each group (control and bulbectomized) consisted of only 5 male mice and 2 female mice. Therefore, a potential sex difference cannot be entirely ruled out and could be a potential avenue for further investigation.
In this model, the olfactory tissue is completely abolished; it would be interesting to determine if functional loss of olfactory input (i.e., via genetic means in the absence of injury) also leads to the development of epilepsy. Furthermore, if the frequency and severity of seizures could be ameliorated by functional restoration of olfactory input in such a model, this would provide a strong basis for further translational investigation of the links between the olfactory system and development and treatment of epilepsy.
It should be noted that there was a fair degree of mortality associated with the bulbectomy surgery, with about one-third of treated mice dying within 1 week. This is similar, however, to other widely used mouse models of epilepsy, such as the systemic pilocarpine model (9). Furthermore, the 100% rate of development of epilepsy following olfactory bulbectomy in the present study indicates that this model is potentially advantageous with respect to minimizing and predicting the number of animals needed in a given study; this is in contrast to the pilocarpine model, in which the development of status epilepticus and subsequent epilepsy is more variable.
In summary, the highlighted study provides an interesting basis to support the use of the model of olfactory bulbectomy in investigating the underlying mechanisms of both posttraumatic epilepsy and the co-morbidity of epilepsy and depression. This model has the advantage of rapid development of epilepsy (within 2 weeks) and a high degree of expression of spontaneous recurrent seizures across individuals. One potential translational caveat to this model is that, so far, no conclusive link has been made between olfactory bulbectomy and the development of either depression or epilepsy in humans. Rodents rely heavily on olfactory and pheromonal cues for proper expression of a wide variety of normal cognitive and reproductive behaviors; as such, they may be particularly prone to developing depressive-like behaviors when these inputs are disrupted. Intriguingly, however, an increased incidence of anosmia in people with depression has been suggested (10), and one study has documented smaller olfactory bulb volume in patients with acute major depression (11). The direction and potential causality of this relationship, however, remain unclear. In addition, a common type of aura experienced by patients with focal epilepsy is phantosmia (olfactory hallucinations), indicating the potential for links between the olfactory system and certain critical brain areas that are prone to harbor epileptogenic foci. The relationship between epilepsy and depression, and the potential contribution of the olfactory system to each disorder separately and as co-morbid entities, promise to be fruitful areas of future research.