Elsevier

Neuropharmacology

Volume 170, 15 June 2020, 108044
Neuropharmacology

Seizure-induced neuroinflammation contributes to ectopic neurogenesis and aggressive behavior in pilocarpine-induced status epilepticus mice

https://doi.org/10.1016/j.neuropharm.2020.108044Get rights and content

Highlights

  • Pilocarpine-induced SE mice displayed neuroinflammation and aggressive behavior in the resident-intruder behavior test.

  • Inhibition of neuroinflammation by minocycline suppressed seizure-induced ectopic neurogenesis in hippocampal DG.

  • Inhibition of neuroinflammation by minocycline suppressed seizure-induced aberrant neuronal migration in hippocampal DG.

  • Inhibition of neuroinflammation by minocycline alleviates aggressive behavior in pilocarpine-induced SE mice.

Abstract

Epilepsy is a chronic neurological disorder often associated with recurrent seizures. A growing body of evidence suggests that seizures cause structural and functional alterations of the brain. It is reported that behavioral abnormalities frequently occur in patients with epilepsy and experimental epilepsy models. However, the precise pathological mechanisms associated with these epilepsy comorbidities remain largely unknown. Neurogenesis persists throughout life in the hippocampal dentate gyrus (DG) to maintain proper brain function. However, aberrant neurogenesis usually generates abnormal neural circuits and consequently causes neuronal dysfunction. Neuroinflammatory responses are well known to affect neurogenesis and lead to aberrant reorganization of neural networks in the hippocampal DG. Here, in this study, we observed a significant increase in neuroinflammation and in the proliferation and survival of newborn granular cells in the hippocampus of pilocarpine-induced status epilepticus (SE) mice. More importantly, these proliferating and surviving newborn granular cells are largely ectopically located in the hippocampal DG hilus region. Our behavior test demonstrated that SE mice displayed severe aggressive behavior. Pharmacological inhibition of neuroinflammation, however, suppressed the ectopic neurogenesis and countered the enhanced aggressive behavior in SE mice, indicating that seizure-induced neuroinflammation may contribute to ectopic neurogenesis and aggressive behavior in SE mice. These findings establish a key role for neuroinflammation in seizure-induced aberrant neurogenesis and aggressive behavior. Suppressing neuroinflammation in the epileptic brain may reduce ectopic neurogenesis and effectively block the pathophysiological process that leads to aggressive behavior in TLE 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.

Section snippets

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).

References (87)

  • J.J. Lin et al.

    Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan

    Lancet

    (2012)
  • R. Madelaine et al.

    MicroRNA-9 couples brain neurogenesis and angiogenesis

    Cell Rep.

    (2017)
  • E.J. Nestler et al.

    Neurobiology of depression

    Neuron

    (2002)
  • E.J. Neuberger et al.

    Enhanced dentate neurogenesis after brain injury undermines long-term neurogenic potential and promotes seizure susceptibility

    Stem Cell Rep.

    (2017)
  • S. Papa et al.

    Early modulation of pro-inflammatory microglia by minocycline loaded nanoparticles confers long lasting protection after spinal cord injury

    Biomaterials

    (2016)
  • J.P. Pierce et al.

    Mossy fibers are the primary source of afferent input to ectopic granule cells that are born after pilocarpine-induced seizures

    Exp. Neurol.

    (2005)
  • R.J. Racine

    Modification of seizure activity by electrical stimulation. II. Motor seizure

    Electroencephalogr. Clin. Neurophysiol.

    (1972)
  • J.S. van Ool et al.

    A systematic review of neuropsychiatric comorbidities in patients with both epilepsy and intellectual disability

    Epilepsy Behav.

    (2016)
  • A. Vezzani et al.

    Epilepsy and brain inflammation

    Exp. Neurol.

    (2013)
  • A. Vezzani et al.

    Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability

    Neuropharmacology

    (2015)
  • A.B. Wisniewski et al.

    Perinatal exposure to genistein alters reproductive development and aggressive behavior in male mice

    Physiol. Behav.

    (2005)
  • X. Zhu et al.

    Neuronal nitric oxide synthase contributes to pentylenetetrazole-kindling-induced hippocampal neurogenesis

    Brain Res. Bull.

    (2016)
  • X. Zhu et al.

    NMDA receptor NR2B subunits contribute to PTZ-kindling-induced hippocampal astrocytosis and oxidative stress

    Brain Res. Bull.

    (2015)
  • X. Zhu et al.

    Decreased CREB levels suppress epilepsy

    Neurobiol. Dis.

    (2012)
  • X. Zhu et al.

    NADPH oxidase activation is required for pentylenetetrazole kindling-induced hippocampal autophagy

    Free Radic. Biol. Med.

    (2016)
  • X. Zhu et al.

    MicroRNA-23a contributes to hippocampal neuronal injuries and spatial memory impairment in an experimental model of temporal lobe epilepsy

    Brain Res. Bull.

    (2019)
  • X.J. Zhu et al.

    Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation

    Neuroscience

    (2006)
  • K.G. Akers et al.

    Hippocampal neurogenesis regulates forgetting during adulthood and infancy

    Science

    (2014)
  • A.P. Aldenkamp et al.

    Behaviour, cognition and epilepsy

    Acta Neurol. Scand. Suppl.

    (2005)
  • J. Altman et al.

    Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats

    J. Comp. Neurol.

    (1965)
  • C. Anacker et al.

    Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus

    Nature

    (2018)
  • M.L. Barker-Haliski et al.

    Neuroinflammation in epileptogenesis: insights and translational perspectives from new models of epilepsy

    Epilepsia

    (2017)
  • M. Bortolato et al.

    NMDARs mediate the role of monoamine oxidase A in pathological aggression

    J. Neurosci.

    (2012)
  • K.O. Cho et al.

    Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline

    Nat. Commun.

    (2015)
  • A.J. Eisch et al.

    Depression and hippocampal neurogenesis: a road to remission?

    Science

    (2012)
  • C.T. Ekdahl et al.

    Inflammation is detrimental for neurogenesis in adult brain

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • S.C. Fagan et al.

    Minocycline development for acute ischemic stroke

    Transl. Stroke Res.

    (2011)
  • R. Frau et al.

    Dysfunctional mesocortical dopamine circuit at pre-adolescence is associated to aggressive behavior in MAO-A hypomorphic mice exposed to early life stress

    Neuropharmacology

    (2019)
  • A. Fuster-Matanzo et al.

    Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches

    Mediat. Inflamm.

    (2013)
  • N. Garrido-Mesa et al.

    Minocycline: far beyond an antibiotic

    Br. J. Pharmacol.

    (2013)
  • S. Jessberger et al.

    Epilepsy and adult neurogenesis

    Cold Spring Harb. Perspect. Biol.

    (2015)
  • S. Jessberger et al.

    Seizure-associated, aberrant neurogenesis in adult rats characterized with retrovirus-mediated cell labeling

    J. Neurosci.

    (2007)
  • B.C. Jobst et al.

    Intractable seizures of frontal lobe origin: clinical characteristics, localizing signs, and results of surgery

    Epilepsia

    (2000)
  • Cited by (0)

    View full text