Abstracts

Rationale:
Depression is the most common comorbidity in patients with epilepsy.  Of interest, patients with major depression are also more susceptible to epilepsy, suggesting a bidirectional relationship.  We used a rat strain bred specifically to exhibit signs of depression to determine if behavioral signs of depression were associated with altered brain inflammation and susceptibility to provoked seizures compared to randomly bred rats.  Our goals were to identify pro-epileptic features in ""depressed"" animals, and to assess whether this could represent a meaningful model to study comorbid depression and epilepsy.
Method:
The Porsolt forced swim test (FST) is commonly used to distinguish rats that exhibit depression-like behaviors.  Rats that spend less time struggling in the FST (Sw-Low rats) compared to ""normal"" (Sw-Nor) rats are commonly taken to exhibit depressed behavior that responds to a variety of antidepressant drugs.  Sprague-Dawley rats identified as Sw-Low in this manner have been selectively interbred at Emory University for 80 generations to develop this ""depressed"" strain.  These animals were used for this project.  Sw-Nor rats were Sprague-Dawley rats obtained from Charles River.  Sw-Low rats of different ages ranging from P30 to P90 were used to assess the age of onset of the Sw-Low phenotype.  Intraperitoneal injection of kainic acid (KA) in males and females after phenotypic onset was used to provoke acute seizures.  We compared the severity and latency to provoked seizures between groups.  Brains were histologically processed 4 days after KA treatment or in age-matched untreated animals for signs of inflammation using immunoreactivity to GFAP to examine astrocyte activation and immunoreactivity to Iba-1 to examine microglial activation. Serial sections of hippocampus cut coronally beginning at the anterior commissure were used for histological analyses.
Results:
The Sw-Low phenotype was not observed at P30, but was clearly seen at P35, indicating that the onset of ""depression"" in Sw-Low rats occurred at an age roughly analogous to a teenage human.  Histological analyses of untreated Sw-Low and Sw-Nor animals at age P37 (after Sw-Low behavioral onset) showed significantly increased baseline GFAP and Iba-1 staining in hippocampus in the Sw-Low group compared to Sw-Nor (n=3 animals per group).  P37 Sw-Low rats further exhibited significantly more severe seizures in response to 20mg/kg KA i.p. (n = 20 per group).  90% of Sw-Low Rats exhibited greater than Stage III seizures (modified Racine scale), whereas only 45% of Sw-Nor rats exhibited greater than Stage III seizures.  Sw-Low rats also exhibited significantly more rapid latency to seizure onset compared to Sw-Nor rats (p< 0.05; n=18 Sw-Low, n=9 Sw-Nor).  Both groups exhibited increased GFAP and Iba-1 staining in hippocampal sections after KA-induced seizures.  However, the higher baseline activation persisted in the Sw-Low group (p< 0.05; n = 3 animals per group).
Conclusion:
These data demonstrated greater baseline measures of neuroinflammation in the form of glial activation in Sw-Low rats, which exhibit depression-like behaviors with a young adult onset.  This suggests a critical association between neuroinflammation and depression.  Furthermore, the Sw-Low group exhibited greater susceptibility to and more severe KA-induced seizures compared to Sw-Nor control rats.  As neuroinflammation is widely viewed to have a critical role in many forms of epilepsy as well as other neurological and psychiatric disease, these data further indicate that the increased baseline neuroinflammation associated with depression-like behavior could be both causal of depression and promote comorbid epilepsy.
Funding:
:None.