Seizure-induced neuroinflammation contributes to ectopic neurogenesis and aggressive behavior in pilocarpine-induced status epilepticus mice
Introduction
Epilepsy is one of the most common neurological disorders that affects approximately 1% of the population worldwide. Epilepsy patients frequently suffer from behavioral, cognitive and psychiatric comorbidities (Aldenkamp and Bodde, 2005, Lin et al., 2012, Watkins et al., 2018), which have a detrimental impact on life quality. A recent systemic review examined the neuropsychiatric comorbidities in epilepsy patients and found that epilepsy patients show increased levels of mood disorders (van Ool et al., 2016). Aggression as a psychiatric comorbidity has been reported in patients with epilepsy and in experimental models (Huang et al., 2012, Sumer et al., 2007, van Elst et al., 2000). Although seizure-induced insults in the brain may constitute a link between the structure alteration and psychiatric comorbidities, the pathological mechanisms are still undetermined.
Neurogenesis persists throughout life in several mammalian species including humans (Altman and Das, 1965). In the adult mammalian brain, neural progenitor cells (NPCs) in the subgranular zone (SGZ) of the hippocampal DG continuously generate new neurons (Goncalves et al., 2016). These newborn neurons migrate to the granular cell layer (GCL), eventually become mature granular cells (GCs) and functionally integrate into the preexisting neuronal network (van Praag et al., 2002). Accurate spatial migration and integration of newborn neurons is pivotal for maintaining physiological functions, while aberrant migration and integration often constitutes abnormal neural circuits and consequently results in brain dysfunctions (Sakai et al., 2018, Scharfman and Pierce, 2012). The function of hippocampal neurogenesis remains unclear; however, a growing number of studies have suggested that newborn neurons in the hippocampus play critical roles in memory formation (Akers et al., 2014, Miller and Sahay, 2019, Shors et al., 2001, Stone et al., 2011) and mood regulation (Anacker et al., 2018, Dellarole et al., 2014, Eisch and Petrik, 2012, Noh et al., 2019, Ransome et al., 2012, Rotheneichner et al., 2014, Santarelli et al., 2003). It is reported that brain injuries stimulate NPC proliferation and increase adult hippocampal neurogenesis (Neuberger et al., 2017, Shapiro, 2017, Yu et al., 2016). Seizure activity strongly affects hippocampal stem-cell associated plasticity (Jessberger and Parent, 2015, Jessberger et al., 2005). Previous studies found that prolonged seizure activity significantly increased proliferation of hippocampal NPCs (Gray and Sundstrom, 1998, Jessberger et al., 2005, Parent et al., 1997). However, these newborn neurons induced by epileptic seizures are usually ectopically located in the DG hilus (Scharfman and Pierce, 2012) and appear to be more excitable than those normally located in the GCL (Zhan and Nadler, 2009, Zhan et al., 2010). A growing body of evidence suggests that neuroinflammation is largely involved in the pathophysiology of epilepsy (Vezzani et al., 2013). It has already been shown that seizure-triggered neuroinflammation significantly affects neurogenesis in the epileptic brain (Ekdahl et al., 2003, Foresti et al., 2011). However, less is known about the effect of this altered neurogenesis on the abnormal behavior.
In this study, we sought to determine whether pilocarpine-induced SE triggers hippocampal neuroinflammation and alters aggressive behavior, and if so, whether this SE-triggered neuroinflammation contributes to a pathophysiological process that leads to ectopic neurogenesis and aggressive behavior in a temporal lobe epilepsy model.
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Animals
Adolescent male C57/BL6 mice (4 weeks old; weighing 19 ± 2 g at the beginning of the experiments) were obtained from the comparative medicine center of Yangzhou University (Yangzhou, China). The animals are allowed to acclimate to their new surroundings for a period of time before they undergo any experimental procedures. The animals were then housed in plastic cages and kept in a regulated environment (22 ± 1 °C) with an artificial 12 h light/dark cycle (lighted from 7:00 a.m. to 7:00 p.m.).
Pilocarpine-induced SE induced hippocampal neuroinflammation
It is generally accepted that seizure activity is associated with inflammatory responses in the brain. To determine whether neuroinflammation is triggered in the hippocampus of a pilocarpine-induced SE model, we measured the inflammatory cytokines IL-1β, IL-6 and TNF-α and the chemokines CCL2, CCL3 and CCL5 at day 4, day 8, day 16 and day 32 after SE in the hippocampus of the pilocarpine-induced SE and vehicle control mice (Fig. 1A). Our data showed that the levels of hippocampal inflammatory
Discussion
Psychiatric disorders are common comorbidities of epilepsy patients. A previous study has shown that pilocarpine-induced SE rats not only developed spontaneous seizures but also exhibited an increased level of aggressive behavior (Huang et al., 2012). However, the cellular and molecular mechanisms that underlie the psychiatric comorbidities of epilepsy are still elusive. Here, in this study, we found that SE mice displayed enhanced aggressive behavior, accompanied by an increased level of
Author contribution statement
Xinjian Zhu designed the research. Xinjian Zhu, Yuanyuan Yao, Jiurong Yang, Qiyue Ge, Diejing Niu, Xiufang Liu and Chenchen Zhang performed the research. Aifeng Zhang and Honghong Yao provided the technical support. Xinjian Zhu analyzed the data and wrote the manuscript. All authors read and approved the final manuscript.
Declaration of competing interest
The authors declare that there are no conflicts of interest.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (81872846 and 81673413 to Xinjian Zhu), Natural Science Foundation of Jiangsu Province (BK20141335 to Xinjian Zhu and BK20151421 to Aifeng Zhang) and the Fundamental Research Funds for the Central Universities (2242017K3DN33 and 2242017K40095 to Xinjian Zhu).
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