Elsevier

Neurobiology of Disease

Volume 93, September 2016, Pages 129-136
Neurobiology of Disease

Environmental enrichment imparts disease-modifying and transgenerational effects on genetically-determined epilepsy and anxiety

https://doi.org/10.1016/j.nbd.2016.05.005Get rights and content

Highlights

  • Early environmental enrichment delays the onset of epilepsy in GAERS.

  • Epilepsy severity and anxiety are also reduced in the next generation.

  • Low levels of CRH mRNA accompany these transgenerational benefits of enrichment.

Abstract

Introduction

The absence epilepsies are presumed to be caused by genetic factors, but the influence of environmental exposures on epilepsy development and severity, and whether this influence is transmitted to subsequent generations, is not well known. We assessed the effects of environmental enrichment on epilepsy and anxiety outcomes in multiple generations of GAERS – a genetic rat model of absence epilepsy that manifests comorbid elevated anxiety-like behaviour.

Methods

GAERS were exposed to environmental enrichment or standard housing beginning either prior to, or after epilepsy onset, and underwent EEG recordings and anxiety testing. Then, we exposed male GAERS to early enrichment or standard housing and generated F1 progeny, which also underwent EEG recordings. Hippocampal CRH mRNA expression and DNA methylation were assessed using RT-PCR and pyrosequencing, respectively.

Results

Early environmental enrichment delayed the onset of epilepsy in GAERS, and resulted in fewer seizures in adulthood, compared with standard housed GAERS. Enrichment also reduced the frequency of seizures when initiated in adulthood. Anxiety levels were reduced by enrichment, and these anti-epileptogenic and anxiolytic effects were heritable into the next generation. We also found reduced expression of CRH mRNA in GAERS exposed to enrichment, but this was not due to changes in DNA methylation.

Conclusions

Environmental enrichment produces disease-modifying effects on genetically determined absence epilepsy and anxiety, and these beneficial effects are transferable to the subsequent generation. Reduced CRH expression was associated with these phenotypic improvements. Environmental stimulation holds promise as a naturalistic therapy for genetically determined epilepsy which may benefit subsequent generations.

Introduction

The manifestation of most diseases results from a complex interaction between an individual's genetic make-up and their environmental exposures, referred to as gene × environment interactions. The epilepsies, comprising of a group of neurological conditions affecting ~ 1% of the population, can be considered prime examples of the result of such interactions (Berkovic et al., 2006). Even the idiopathic generalised epilepsies – considered to be largely of complex genetic origin – do not show 100% concordance in monozygotic twin studies, implicating environmental influences in their causation (Berkovic et al., 1998, Briellmann et al., 2001). Also, in large families with epilepsy due to highly penetrant single gene mutations, significant heterogeneity exists between the specific epilepsy syndrome experienced by family members, as does non-expression of the disease in some members harbouring the causative mutation (Dibbens et al., 2013, Steinlein et al., 1995), further supportive that other influential environmental insults or conditions are important in the manifestation of epilepsy.

Environmental factors are recognised as strong precipitants of psychiatric disorders, including anxiety and depression. In particular, chronic stress experienced either in early life or in adulthood, appears to predispose to the development of these disorders (Caspi et al., 2003, Kessler, 1997, Van Praag et al., 2004). However, not all people who experience chronic stressors develop psychiatric problems, implicating other factors, such as genetic vulnerabilities, in their causation. Understanding the relationships mediating gene × environment interactions may therefore provide insight into the mechanisms driving both neurological and psychiatric disorders. This may be most relevant for epilepsy, since many patients with epilepsy experience psychiatric disorders. In addition, gene × environment interactions may also be important mediators of disease phenotype in subsequent generations. For example, early life trauma in the first generation leads to subsequent cognitive deficits (Bohacek et al., 2015) and increased depressive-like behaviour (Franklin et al., 2010) in subsequent generations. The mechanisms driving such heritability appear to be epigenetic, potentially via DNA methylation, microRNA, or retrotransposons (Gapp et al., 2014, Roth et al., 2009, Whitelaw and Martin, 2001). To our knowledge, heritability of environmental influences on disease phenotype has not been investigated in genetically-determined epilepsy.

Converse from the effects of stressful environments, stimulating exposures, such as physical activity and exercise, appear to induce anxiolytic and antidepressant effects (Strohle, 2009). An extensive body of experimental work using environmental enrichment (EE), described as ‘a combination of complex inanimate and social stimulation’ (Rosenzweig et al., 1978), concurs with the clinical literature: housing rodents in environmentally enriched conditions causes improvements in anxiety and depressive-like behaviours, as well as in a variety of neurological conditions, compared to standard housed rodents (Nithianantharajah and Hannan, 2006). Although the mechanisms mediating these environmentally-mediated effects are complex, and may vary with the disease studied, one study has reported that environmental enrichment mediates its anxiolytic effects via changes in corticotrophin-releasing hormone (CRH) signalling (Sztainberg et al., 2010).

Several reports document the effects of environmental enrichment on epilepsy development and seizure susceptibility. Using a variety of genetic and acquired epilepsy models, as well as those exhibiting focal and primary generalised seizures, the large majority of these studies demonstrate that continuous housing in enriched environments reduces seizure susceptibility and the severity of the epilepsy. One article particularly relevant to the current study utilised the WAG/Rij genetic rat model of absence epilepsy and found the opposite result, such that epileptic rats housed in large groups (8–10/cage) in an enriched environment showed more frequent and longer seizures (Schridde and van Luijtelaar, 2004) compared to those housed singly in impoverished conditions.

Another well-validated rat model of absence epilepsy is the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model (Jones et al., 2011, Marescaux et al., 1992), which we use in the current study. These rats experience absence seizure-like events accompanied with spike-wave discharges on the EEG from about 9 weeks of age in our hands. The epilepsy is polygenic in origin (Rudolf et al., 2004), with a mutation in a T-type calcium channel contributing to the disease phenotype (Powell et al., 2009). GAERS also possess a highly anxious and depressive phenotype (Jones et al., 2008), as well as endophenotypes relevant to psychosis (Jones et al., 2010), promoting this model as a valuable tool with which to study the causal connections between epilepsy and psychiatric disorders commonly observed in epilepsy. Here, we use GAERS to examine gene × environment interactions, investigating whether environmental enrichment imparts disease-modifying effects on the epilepsy and on the anxiety disorder. Because the phenotype(s) of GAERS are presumed to be genetically determined, we also investigated whether any environmentally mediated effects are heritable to the next generation in a Lamarkian fashion. Finally, we investigate CRH signalling as a mechanism underlying any environmental effects.

Section snippets

Animals

Genetic Absence Epilepsy Rats from Strasbourg (GAERS; n = 97) sourced from our GAERS-Melb colony (Powell et al., 2014) were used in this study. They were bred in the Biological Research Facility of the Department of Medicine (RMH), University of Melbourne. All animals were housed under a 12-hour light-dark cycle, with food and water available ad libitum. All animal experiments were conducted with prior approval from the University of Melbourne Animal Ethics Committee.

Housing conditions

Rats were housed in one of

Early environmental enrichment delays epileptogenesis and reduces disease severity

In the first experiment, rats were housed either in environmentally enriched cages or in standard cages from weaning, and EEG recordings performed from 9 weeks of age onward. We found that enrichment produced a significant anti-epileptogenic effect by delaying the onset of epilepsy, as evidenced by a reduced proportion of rats which had developed epilepsy by 9 weeks of age (3/7) compared with standard housed rats (8/8; χ2 = 5.8, p = 0.016; Fig. 1A). While all GAERS did subsequently develop epilepsy,

Discussion

Genes and environmental exposures interact to create vulnerability and resilience for a range of different disorders, including neurological and psychiatric conditions (Caspi and Moffitt, 2006, Hunter, 2005). We are only to beginning to understand the scope of these interactions, how they cause disease, and how the adopted mechanisms might be harnessed to develop disease-modifying therapies. Here we demonstrate, using a model of genetically determined epilepsy comorbid with high anxiety, that

Acknowledgments

TO, MS, MM, NJ received funding from the NHMRC project grant scheme for this work (#566843 and #1059860). NJ received funding from the NHMRC Career Development Award scheme (#628466) and from the ARC Future Fellowship scheme (#13100100). The remaining authors report no conflicts of interest associated with this work.

References (56)

  • N.C. Jones

    Morphometric changes and molecular mechanisms in rat models of idiopathic generalized epilepsy with absence seizures

    Neurosci. Lett.

    (2011)
  • S.M. Korbey

    Seizure susceptibility and locus ceruleus activation are reduced following environmental enrichment in an animal model of epilepsy

    Epilepsy Behav.

    (2008)
  • M.R. Rosenzweig

    Social grouping cannot account for cerebral effects of enriched environments

    Brain Res.

    (1978)
  • T.L. Roth

    Lasting epigenetic influence of early-life adversity on the BDNF gene

    Biol. Psychiatry

    (2009)
  • J.A. Arai

    Transgenerational rescue of a genetic defect in long-term potentiation and memory formation by juvenile enrichment

    J. Neurosci.

    (2009)
  • S.F. Berkovic

    Epilepsies in twins: genetics of the major epilepsy syndromes

    Ann. Neurol.

    (1998)
  • J. Bohacek

    Pathological brain plasticity and cognition in the offspring of males subjected to postnatal traumatic stress

    Mol. Psychiatry

    (2015)
  • R.S. Briellmann

    Causes of epilepsies: insights from discordant monozygous twins

    Ann. Neurol.

    (2001)
  • A. Caspi et al.

    Gene-environment interactions in psychiatry: joining forces with neuroscience

    Nat. Rev. Neurosci.

    (2006)
  • A. Caspi

    Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene

    Science

    (2003)
  • J.P. Curley

    Social enrichment during postnatal development induces transgenerational effects on emotional and reproductive behavior in mice

    Front. Behav. Neurosci.

    (2009)
  • G. Dezsi

    Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy

    Epilepsia

    (2013)
  • L.M. Dibbens

    Mutations in DEPDC5 cause familial focal epilepsy with variable foci

    Nat. Genet.

    (2013)
  • E. Elliott

    Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice

    Nat. Neurosci.

    (2010)
  • M.M. van Gaalen

    Effects of transgenic overproduction of CRH on anxiety-like behaviour

    Eur. J. Neurosci.

    (2002)
  • K. Gapp

    Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice

    Nat. Neurosci.

    (2014)
  • D. Gauguier

    Chromosomal mapping of genetic loci controlling absence epilepsy phenotypes in the WAG/Rij rat

    Epilepsia

    (2004)
  • D.C. Hesdorffer

    Major depression is a risk factor for seizures in older adults

    Ann. Neurol.

    (2000)
  • Cited by (38)

    View all citing articles on Scopus
    View full text