Clin Genet 2010: 78: 321 – 333 Printed in Singapore. All rights reserved  2010 John Wiley & Sons A/S CLINICAL GENETICS doi: 10.1111/j.1399-0004.2010.01503.x Developmental Biology: Frontiers for Clinical Genetics Section Editors: Jacques L. Michaud, e-mail: jacques.michaud@recherche-ste-justine.qc.ca Olivier Pourqui´ e, e-mail: pourquie@igbmc.fr Hippocampus development and function: role of epigenetic factors and implications for cognitive disease Lagali PS, Corcoran CP, Picketts DJ. Hippocampus development and function: role of epigenetic factors and implications for cognitive disease. Clin Genet 2010: 78: 321–333.  John Wiley & Sons A/S, 2010 The hippocampus is a primary region of the brain controlling the formation of memories and learned behaviours. The ability to learn or form a memory requires a neuron to translate a transient signal into gene expression changes that have a long-lasting effect on synapse activity and connectivity. Numerous studies over the past decade have detailed changes in epigenetic modifications under various learning paradigms to support a role for chromatin remodelling in these processes. Moreover, the identification of mutations in epigenetic regulators as the cause of mental retardation or intellectual disability (MR/ID) disorders further strengthens their importance to learning and memory. Animal models for many of these disorders are emerging and advancing our understanding of the molecular mechanisms linking epigenetic regulation and cognitive function. Here, we review how chromatin remodelling proteins implicated in MR/ID contribute to the development of the hippocampus and memory formation. Conflict of interest The authors declare no competing conflicts, financial or otherwise. PS Lagali a,b* , CP Corcoran a,b* and DJ Picketts a,b a Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada, and b Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada ∗ These authors contributed equally to this work. Key words: chromatin remodelling – cognitive disease – epigenetics – hippocampus – intellectual disability – learning and memory – mental retardation Corresponding author: David J. Picketts, PhD, Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. Tel.: 613-737-8989; fax: 613-737-8803; e-mail: dpicketts@ohri.ca Received 25 June 2010, revised and accepted for publication 2 July 2010 Epigenetic modification of the genome is a major point of regulation governing many developmental processes. In the central nervous system (CNS), epigenetic regulators play crucial roles during development in the transition of a multipotent neu- roprogenitor to a committed neuron, in the gener- ation of the vast number of specialized cell types and their specific gene expression profiles, and for cell survival and neuronal plasticity in response to external and intrinsic signals (1–3). Epigenetic processes primarily impinge on the basic subunit of chromatin, the nucleosome, which is comprised of 146 base pairs of DNA wrapped around an octamer of two copies each of histones H2A, H2B, H3, and H4. Alteration in chromatin compaction is a dynamic process regulating gene expression and it can be modified by several mechanisms including DNA methylation, the post-translational alteration of the histones (acetylation, methylation, phosphorylation, ADP-ribosylation, sumoylation, and ubiquitination), or by ATP-dependent nucleo- some remodelling machines (Fig. 1). The covalent 321