Factors associated with predisposition and vulnera- bility to neurodegenerative disorders may be described usefully within the context of gene-envi- ronment interplay. There are many identified genet- ic determinants for so-called genetic disorders, and it is possible to duplicate many elements of recog- nized human neurodegenerative disorders in either knock-in or knock-out mice. However, there are similarly, many identifiable environmental influ- ences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. Constituent cellular defense mechanisms responsive to the challenge of increased reactive oxygen species represent only one crossroad whereby environment can influence genetic predisposition. In this paper we highlight some of the major neurodegenerative disorders and discuss possible links of gene-environ- ment interplay. The process of adult neurogenesis in brain is also presented as an additional element that influences gene-environment interplay. And the so- called priming processes (i.e., production of recep- tor supersensitization by repeated drug dosing), is introduced as yet another process that influences how genes and environment ultimately and co- dependently govern behavioral ontogeny and out- come. In studies attributing the influence of genetic alteration on behavioral phenotypy, it is essential to carefully control environmental influences. Keywords: Neurodevelopment Neurodegeneration; Neurodevelopment; Neurogenesis; Alzheimer disease; Huntington disease; Tau neuropathy; Priming INTRODUCTION Most of the neurodegenerative disorders that have received some degree of documentation, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are characterized by neuronal damaged caused putatively by toxic, abnormal, aggregate-prone proteins or 'clusters'. A recent review by Petrucelli and Dawson (2004) outlines and describes three different aspects of neurodegenerative mechanisms involved in these disorders, as follows: (1) the genetic configura- tion underlying the abnormal processing and accumu- lation of misfolded proteins in the neurodegenerative diseases, using PD as a model disorder, (2) an under- standing and consideration of the cellular mechanisms for disposal of abnormal proteins, and the effects of toxic protein accumulation on the ubiquitin proteasome system and neuronal survival, and (3) the development and challenges offered by cell culture and animal mod- els leading to rational and effective treatment strate- gies. In the realm of neurodegeneration, there are known genetically-associated disorders such as ALS/motor neuron disease, HD, early-onset PD, myas- thenia gravis, and others. ALS/motor neuron disease can be inherited or acquired by consumption of foods containing a high content of abnormal excitatory amino acids. HD is an autosomal dominant disorder, caused by abnormal expansion in the length of a CAG triplet repeat sequence in a gene on chromosome 4 (i.e., the huntingtin gene). Myasthenia gravis can be autosomal and dominantly inherited; or caused by thymus-derived F.P. Graham Publishing Co. Neurotoxicity Research, 2004, VOL. 6(6). pp. 415-434 Gene-Environment Interplay in Neurogenesis and Neurodegeneration TOMÁS PALOMO a , TREVOR ARCHER b , RICHARD J. BENINGER c and RICHARD M. KOSTRZEWA d, * a Servicio Psiquiátrico, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041 Madrid, Spain; b Department of Psychology, University of Göteborg, Box 500, SE-40530 Göteborg, and Department of Health and Behavioural Science, University of Kalmar, Kalmar, Sweden; c Departments of Psychology and Psychiatry, Queen's University, Kingston ON K7L 3N6, Canada; d Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. kostrzew@etsu.edu (Received 30 September 2004; Revised 19 October 2004; In final form 23 November 2004) *Corresponding author. Tel.: 1 423 439-6321; Fax: 1 423 439-8773; E-mail: Kostrzew@etsu.edu ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2004 FP Graham Publishing Co., www.NeurotoxicityResearch.com