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