Our data provide evidence that rapid kindling in young animals is accompanied by sustained changes in forced swimming and taste preference tests that can be interpreted as behavioral correlates of depression.
In contrast to conventional kindling, rapid kindling is not regarded as a permanent condition: while conventional kindling leads to enhanced brain excitability and the susceptibility to seizures lasts for the lifetime [33
], the changes after rapid kindling tend to disappear gradually [17
]. Indeed, in our studies, afterdischarge threshold returned to baseline values in as early as two weeks, and afterdischarge duration- four weeks after kindling. Yet, certain key long-lasting features of kindling state were observed after rapid kindling. Increased afterdischarge duration was recorded two weeks after kindling. Threshold stimulation, which had been subconvulsant in naïve animals, evoked behavioral seizure responses both at 2 and 4 weeks after kindling (even though the severity of seizures declined as a function of time). Thus, rapid kindling is capable of inducing neural plasticity that lasts for at least several weeks, and which translates into the enhanced seizure response.
An important advantage of rapid kindling over conventional protocol is the “compressed” duration of epileptogenesis, which allows reproducing the progression of epileptic process within certain developmental stage of the animal. This is not possible with conventional kindling, since rapid ontogenic development of experimental animals outpaces the evolution of kindling process. In contrast to post-status epilepticus epilepsy, kindling is not accompanied by hippocampal sclerosis and spontaneous seizures. Eliminating spontaneous seizures as a variable permits this model to accommodate an important clinical feature of epilepsy-associated depression observed by Attarian et al [34
] and Quigg et al [35
]. Those authors found that the prevalence depression was independent of the degree of seizure control. Caplan and associates [6
] did not find an association between seizure variables and affective disorders in children. Rapid kindling provides an opportunity to focus on neuronal plastic changes that underlie behavioral abnormalities without concerns regarding if behavioral testing was affected by post-ictal state et cetera
Reports on depression-like disorders associated with experimental limbic epilepsy (an experimental correlate of TLE), particularly kindling, are scarce and controversial. Cannizzaro et al [36
], Sabatino et al [37
], Helfer et al [38
], Ma and Leung [39
], Witnick et al [40
], did not find changes in FST and in taste preference in the animals kindled with either pentylenetetrazole, or amygdala stimulation. In contrast, Mortazavi et al [41
] found that pentylenetetrazole-kindled animals showed increased immobility time in FST. Animals in that study received chronic chemical provocation with pentylenetetrazole and had sustained hippocampal injury.
Correlating symptoms of depression in humans with behavioral patterns of depression in the rat is a challenge, and cannot rely on a single behavioral test. Similar to humans, in whom depression is associated with behavioral, vegetative, and biochemical variables [27
], experimental animals should exhibit a variety of behavioral, vegetative, and biochemical abnormalities in order to satisfy the definition of depression; the importance of a combination approach in evaluating depression in animal models is emphasized by the fact that an important symptom of depression, suicidality, cannot be reproduced in experimental animals. We used two behavioral tests, which are most commonly applied for studying depressive behavior in rodents: FST and taste preference.
Rapid kindling led to the sustained changes in FST. Kindled animals showed significant increase in immobility time. Interestingly, the extent of these changes positively correlated with the severity of behavioral seizures elicited by threshold stimulation on both one day and 4 weeks after kindling in individual animals. This suggests that even though animals did not exhibit spontaneous seizures, the strength of neuronal plastic changes (that translated to the severity of seizures in response to threshold stimulation) affects the extent of such feature of depression as the inability to adopt an active strategy under an inescapable stressful situation.
Loss of taste preference which can be interpreted as anhedonia was also observed in kindled animals. In saccharin consumption test, this was observed at both 2 and 4 weeks after rapid kindling. Surprisingly, in the sucrose consumption test 4 weeks after kindling, the animals’ behavior was reversed from the loss of preference to enhanced preference, even if compared to naïve subjects. In contrast to saccharin, sucrose has caloric value. It has been known that depression can be accompanied by both loss and the increase of appetite [21
]; furthermore, antidepressant drugs, such as selective serotonin reuptake inhibitors, are commonly known to reduce appetite and curb weight gain [42
]. Since the increase of taste preference in sucrose test 4 weeks after kindling can be excluded based on saccharin test, it is conceivable that increased sucrose intake reflects increased appetite. Studies are underway with food consumption to confirm this suggestion.
In summary, the important findings in this report are: 1) the evolution of depressive behavior accompanying epileptogenesis can be modeled in young animals 2) epilepsy associated depressive behavior can be demonstrated in this model without either overt brain injury or ongoing spontaneous seizures. Upon further validation, which would include both expanded behavioral and biochemical assays, our model can provide a good platform for evaluating pharmacological interventions to treat depression in epilepsy.