title: Environmental enrichment imparts disease-modifying and transgenerational effects on genetically-determined epilepsy and anxiety.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Gabi
authors.initials: G
authors.lastname: Dezsi
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ezgi
authors.initials: E
authors.lastname: Ozturk
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Victoria, Australia; Department of Psychiatry, St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Salzberg
authors.affiliation: Department of Pharmacology and Physiology, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Margaret
authors.initials: M
authors.lastname: Morris
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Victoria, Australia. Electronic address: ncjones@unimelb.edu.au.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001008:Anxiety Disorders / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000503:physiopathology*; D004195:Disease Models, Animal; D004777:Environment; D004832:Epilepsy, Absence / Q000235:genetics*; D051381:Rats; D012640:Seizures / Q000150:complications*
keywords: Anxiety; CRH; DNA methylation; Environmental enrichment; Epilepsy; GAERS; Gene×environment interaction; Transgenerational inheritance