The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases

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Perspective

Molecular Psychiatry (2009) 14, 992–1003; doi:10.1038/mp.2009.82

D K Lahiri^1,2, B Maloney¹ and N H Zawia³

1. Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
2. Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
3. Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA

Correspondence: Dr DK Lahiri, Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, 791 Union Drive, Indiana University School of Medicine, Indianapolis, IN 46202, USA. E-mail: dlahiri@iupui.edu

Received 16 February 2009; Revised 29 May 2009; Accepted 17 June 2009.

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Abstract

Neurobiological disorders have diverse manifestations and symptomology. Neurodegenerative disorders, such as Alzheimer's disease, manifest late in life and are characterized by, among other symptoms, progressive loss of synaptic markers. Developmental disorders, such as autism spectrum, appear in childhood. Neuropsychiatric and affective disorders, such as schizophrenia and major depressive disorder, respectively, have broad ranges of age of onset and symptoms. However, all share uncertain etiologies, with opaque relationships between genes and environment. We propose a 'Latent Early-life Associated Regulation' (LEARn) model, positing latent changes in expression of specific genes initially primed at the developmental stage of life. In this model, environmental agents epigenetically disturb gene regulation in a long-term manner, beginning at early developmental stages, but these perturbations might not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene, specifically through changes in methylation and oxidation status within the promoter of specific genes. The LEARn model combines genetic and environmental risk factors in an epigenetic pathway to explain the etiology of the most common, that is, sporadic, forms of neurobiological disorders.