Rats bred for susceptibility to depression-like phenotypes have higher kainic acid-induced seizure mortality than their depression-resistant counterparts

Abstract

Epidemiological evidence suggests that epilepsy and depression are comorbid diseases. In fact, depression is the most common neuropsychiatric disorder associated with epilepsy, particularly temporal lobe epilepsy, and individuals with a history of depression are at a higher risk for developing epilepsy than the general population. Despite the epidemiological evidence for this link, there has been little experimental evidence to support the connection or elucidate possible underlying mechanisms. In an effort to address this problem and develop an animal model of epilepsy and depression comorbidity, we assessed seizure susceptibility and severity parameters in rats selectively bred for either susceptibility (the SwLo, SUS, and HYPER lines) or resistance (the SwHi, RES, and MON RES lines) to depression-like phenotypes. We found that rats bred for susceptibility to depression-like phenotypes experienced higher mortality following kainic acid-induced seizures than their resistant counterparts. In contrast, most line differences were not recapitulated when flurothyl was used to elicit seizures. Stress reduced kainic acid-induced mortality rates in all lines except the HYPER rats, supporting previously established indications that the stress response of HYPER rats is abnormal. These combined results support a neurobiological link between epilepsy and depression, advancing us towards an animal model of their comorbidity.

Fig. 1

Kainic acid-induced seizures. Kainic acid was administered to rats at a dose of 10 mg/kg, followed by 5 mg/kg booster injections until a clonic-tonic seizure was produced. Shown is (A) mortality, with the number of animals that died over the total tested above each bar, and (B) the cumulative kainic acid dose (mean±SEM) required to produce a CT seizure. * P <0.05 for the depression-susceptible line compared to its depression-resistant counterpart (SwLo vs SwHi, SUS vs RES, HYPER vs MON RES, respectively).

Fig. 2

Flurothyl-induced seizures. Flurothyl was administered to rats at a rate of 20 μL/min, and latency to CT seizure was observed. Shown is latency to CT seizure (mean±SEM) for each line. N = 6–16 per group. * P <0.05 for the depression-susceptible line compared to its depression-resistant counterpart (SwLo vs SwHi, SUS vs RES, HYPER vs MON RES, respectively).

Fig. 3

The effects of stress on kainic acid-induced seizures. Kainic acid-induced seizures were assessed following exposure of the rats to stress paradigms used to produce the depression-like phenotype in each line. SUS and RES rats were exposed to 30 minutes of 90–95 dB white noise in a novel environment, while HYPER, MON RES, and NS control rats received 3 hours of tail shock. Shown is (A) mortality, with the number of animals that died over the total tested above each bar, and (B) the cumulative kainic acid dose (mean±SEM) required to produce a CT seizure. * P <0.05 compared to the no-stress condition for each line.

Fig. 4

The effects of stress on flurothyl-induced seizures. Flurothyl-induced seizures were assessed following exposure of the rats to stress paradigms used to produce the depression-like phenotype in each line. SUS and RES rats were exposed to 30 minutes of 90–95 dB white noise in a novel environment, while HYPER, MON RES, and NS control rats received 3 hours of tail shock. NS control rats also received 3 hours of tail shock. Shown is latency (mean±SEM) to CT seizure following flurothyl administration (20 μL/min). N = 6–18 per group. * P <0.05 compared to the no-stress condition for each strain.