Depression Induced by Early-life Hypoxic Seizures: Pathogenesis and Molecular Alterations

Abstract

Background: Children with epilepsy are more likely to develop depression which reduces their quality of life and leads to higher suicide risks in adolescence. The treatment of depression that accompanies epilepsy is understudied and effective therapeutic approaches remain elusive, let alone the fact that some antidepressant drugs have proconvulsant properties, increasing the risk of seizures. This renders the treatment of depression in pediatric patients suffering from epilepsy even more challenging. Thus, improving our understanding of the molecular pathways involved in epilepsy and depression is fundamental to optimize therapeutic strategies. Prior work in our rat model of neonatal hypoxic encephalopathy revealed the emergence of peri-adolescent depressive-like behaviors following early life hypoxic seizures (HS), potentially via HS-induced hippocampal TrkB (tropomyosin-related kinase) receptor pathway dysfunction. Investigating whether the mechanisms of depression induced by early-life HS are similar to those of major depression holds an important translational clinical value. Sertraline, a standard clinically employed antidepressant, is a serotonergic drug that was also shown to exert a serotonin-related modulation of the TrkB pathway in rodent models of major depressive disorders. Here, we aimed to investigate whether sertraline is effective against HS-induced depression and to assess possible molecular alterations mediating HS-induced deficits.

Methods: Hypoxia was induced in postnatal day 10 (P10) rat pups while the rest remained under normoxic conditions. Only pups that experienced 6 seizures or more were included in this study. The rats were then divided into 4 groups: NV (normoxic with vehicle water), HV (hypoxic seizure with vehicle water), NSERT (normoxic with sertraline), and HSERT (hypoxic seizure with sertraline). Sertraline was administered via drinking water between P24 and P30. Depressive-like and anxiety-like behaviors were then investigated in the forced swim test (P25-26) and the open field test (P27), sequentially. Rats were sacrificed at P30. Potential neuronal cell loss and alteration in synaptic plasticity were assessed through immunohistochemistry via Neu-N and synaptophysin (SYP) staining, respectively.

Results: Rats in both HV and HSERT groups had a comparable number of seizures (p>0.05). Rats’ weight and water consumption were comparable among all groups between P21 and P30 (p>0.05). During the first testing day of the forced swim test, the HV group revealed increased immobility when compared to controls (NV) (p<0.05). HSERT immobility percentages were comparable to those of the NV group (p>0.05). Nonetheless, during the second testing day, NV and HV groups had a comparable immobility time (p>0.05), with a lower immobility percentage observed in HSERT and NSERT groups when compared to NV and HV (p<0.05). During the first testing day of the FST, the high activity percentages of HV, NV, and NSERT groups were comparable (p>0.05). However, the high activity time of the HSERT group was significantly higher than that of the NSERT group (p<0.05). On the second testing day, both NV and HV had comparable high activity percentages (p>0.05), while the HSERT group had a high activity percentage significantly higher than that of both NV and HV (p<0.05). In the open field test, the cumulative total distance traveled by the HV rats was significantly lower than that of the NV group (p<0.05). The HSERT group had a total distance traveled comparable to that of the HV and NSERT groups (p>0.05). The HV group traveled a total distance in the open field significantly lower than that of the NV group (p<0.05). The HSERT group traveled a total distance significantly lower than that of the NV group (p<0.05), but comparable to that of the HV group (p>0.05). The NSERT group traveled a total distance significantly lower than that of the NV group (p<0.05). HV rats spent significantly more time and traveled less in the periphery when compared to NV (p<0.05). The HSERT and HV groups traveled a comparable distance in the periphery (p>0.05), but the HSERT group spent more time in the periphery when compared to HV (p<0.05). The NSERT group spent more time in the periphery when compared to NV (p<0.05). The HV group spent a significantly lower time and traveled a smaller distance in the center when compared to NV (p<0.05). The HSERT group spent a significantly lower time and traveled a smaller distance in the center when compared to NV (p<0.05). HV and HSERT groups had a similar distance traveled in the center, but the HSERT group spent less time in the center when compared to HV (p<0.05). The NSERT group spent a significantly lower time and traveled a smaller distance in the center when compared to NV (p<0.05). Preliminary histological data revealed comparable neuronal densities in all groups; however, SYP seems to be overexpressed in the prefrontal cortex and the hippocampus of HV rats in the hilar and CA2-3 regions when compared to NV.

Conclusion: Our early-life hypoxic-seizure model successfully recapitulates depressive-like and anxiety-like behaviors in peri-adolescent rats similar to the behavioral defects observed in pediatric patients who have suffered from perinatal hypoxic-ischemia. Short-term sertraline administration reversed depressive-like behaviors in the treated rats; however, it failed to reverse and exacerbated hypoxic seizure-induced anxiety. These effects on anxiety and depression are commonly observed early in the treatment course with antidepressants. The hypoxic-seizure-associated behavioral deficits seem to be mediated by maladaptive changes in markers of synaptic plasticity. These results confirm cognitive and emotional behavioral derangements correlated with early-life hypoxic seizures highlighting the necessity of treating seizure-associated behavioral comorbidities. Investigating the effects of a longer treatment duration will help determine if sertraline’s chronic administration holds anxiolytic effects and will depict its optimal use in children who have suffered from hypoxic seizures.