neuroscientists, clinicians and geneticists with interests in disease, given the ever-increasing number of synaptic pro- teins that are involved in human brain diseases such as Alzheimer’s disease, autism, mental retardation and schi- zophrenia (5). G2Cdb can be freely accessed at www.genes2cogni tion.org. CONSTRUCTION AND CONTENTS G2Cdb consists of a catalogue of experimentally validated mammalian synapse genes that we have integrated with genomic annotation resources, studies of naturally occur- ring gene mutations found in the human central nervous system (CNS) diseases, brain gene expression resources, as well as behavioural studies and electrophysiological stud- ies using genetically modiﬁed mice. The database crea- tion was split into six principle steps (i) compiling a catalogue of mammalian synapse genes from proteomic studies, (ii) attaching gene symbols, protein names and their synonyms to the genes, (iii) constructing gene lists to represent the constituents of synaptic protein complexes and organelles, (iv) linking to external genome and mole- cular resources, (v) linking to transcript and protein exp- ression resources, and (vi) automated text-mining and then human (manual) curation of published literature. Details for each of these are presented in the following sections. Compiling a catalogue of mammalian synapse genes The proteomic study of synaptic organelles and receptor– protein complexes biochemically isolated from nervous tissue gives us the best current picture of the components of the mammalian synapse. These studies utilize a series of puriﬁcation strategies, followed by liquid chromatography tandem mass spectroscopy and/or large scale immuno- blotting to identify proteins (6). We have extracted the data from seven large-scale pro- teomic proﬁling studies to populate G2Cdb (Table 1), thus creating a comprehensive set of proteins found at the mammalian synapse. In total, more than 1100 proteins have been identiﬁed revealing an unexpected complexity Paper Molecular characterization and comparison of the components and multiprotein complexes in the post-synaptic proteome. Identiﬁcation and veriﬁcation of novel rodent post-synaptic density proteins. Proteomics analysis of rat brain post-synaptic density. Implications of the diverse protein functional groups for the integration of synaptic physiology. Semiquantitative proteomic analysis of rat forebrain post-synaptic density fractions by mass spectrometry. Molecular constituents of the post-synaptic density fraction revealed by proteomic analysis using multidimensional liquid chromatography-tandem mass spectrometry. Identiﬁcation of activity-regulated proteins in the post-synaptic density fraction. Identiﬁcation of proteins in the post-synaptic density fraction by mass spectrometry. Table 1. Published synapse proteomic proﬁling datasets used in the production of G2Cdb Nucleic Acids Research, 2009, Vol. 37, Database issue D847 to the synapse which is also reﬂected in its complex evolu- tionary origin (7). We refer to this set as the PSP (2) and this is the current focus of G2Cdb. As the next step in creating a mammalian synapse gene catalogue, we took the set of 1124 proteins found in the PSP and mapped the protein sequences back to the mouse genome via the Ensembl genome annotation database. Next, we used all-versus-all protein and transcript FASTA (8) searches to ensure the resulting mouse gene set was non-redundant and then assigned unique identi- ﬁers to these genes (of the form ‘Gxxxxxxxx’ where x is a digit 0–9). We found unique identiﬁers were necessary as genome database identiﬁers changing regularly in mam- malian genomes, particularly in diﬃcult-to-predict, multi- exon genes. Having our own identiﬁers insulates G2Cdb from such changes. We also store and display homologous gene informa- tion for all G2Cdb genes. To date, we have focused on orthology information, utilizing the automated Ensembl predictions as a starting point. We found it valuable to manually curate gene orthology information particularly where clear 1:1 relationships between the human and mouse genes could not be automatically obtained. Such orthologues were manually assigned by searching using the mouse and human gene names on the Mouse Genome Informatics (MGI; 9) and HUGO Gene Nomenclature Committee (HGNC; 10) database websites, respectively. Where this did not provide a match, sequence similarity was used to assign orthologues. Gene symbols, protein names and their synonyms Diﬀerent research communities (e.g. neuroscience or genetics) for historical reasons have often favoured the use of diﬀerent names or symbols when referring to the same biological entities. We address this by labelling genes with approved gene symbols and additionally stored terms and synonyms obtained from various sources including the gene nomenclature committees (MGI and HGNC) and standardized protein names (UniProt; 11). This means the user can select from either standard names or use common synonyms employed in their ﬁeld when searching. Year 2006 2004 2004 2004 2004 2002 2000 Reference Collins et al. (2) Jordan et al. (30) Li et al. (31) Peng et al. (32) Yoshimura et al. (33) Satoh et al. (34) Walikonis et al. (35)