recent developments in genomics , proteomics and systems biology have significantly impacted fields such as oncology and immunology ( 15 ) and are beginning to be applied to neuroscience research , generating an exponentially increasing amount of data ( 611 ) and calling for efficient databases .
for instance , databases listed in the society for neuroscience database gateway ( ndg , ) principally contain imaging , anatomic or clinical data , while few focus on the gene or protein level and their functions .
the synapse is a specialized intercellular junction between neurons or between neurons and other excitable cells such as muscle .
the synapse plays a key role in information processing in the nervous system that underlies many neurobiological processes , including neurotransmission , learning and memory .
defects in synaptic activity are associated with many neurological disorders , including alzheimer 's disease ( 12 ) .
the synapse has also been proposed as an excellent candidate for large - scale systems biology studies ( 7,8,13 ) .
there is a critical need for a focused yet comprehensive database resource for the synapse 
proteome. creating such a database is non - trivial , because the proteins involved in synaptic activities are numerous and diverse and information is scattered in multiple heterogeneous sources .
no simple keyword search and no small number of domains can retrieve all the proteins .
these complexities may explain why such a database has not been reported thus far . here ,
we present the synapse protein database ( syndb , ) as an information hub for synapse - related proteins .
it describes a domain using a collection of concepts or terms and includes the hierarchical relationships between the terms . in order to formally describe synaptic functions and structures
, we extensively reviewed three sources of information : ( i ) three classic text books , synapses ( 15 ) , principles of neural science ( 16 ) and ion channels of excitable membranes ( 17 ) ; ( ii ) 115 recent ( 20002006 ) review papers published in nature reviews neuroscience and annual review of neuroscience ; and ( iii ) relevant terms in two general ontologies , gene ontology ( go ) ( 18 ) and medical subject headings ( mesh ) ( 19 ) . by reviewing these resources and iteratively organizing the information
, we constructed the first synapse ontology ( syno ) , a hierarchical description of synaptic structures and functions .
structure is divided into categories such as presynaptic compartment , postsynaptic compartment and glia ; and function is divided into categories such as transmitter release and endocytosis , synapse formation and signal transduction in the postsynaptic neuron . in total , syno contains 177 terms with hundreds of synonyms and up to eight levels deep .
syno is constructed , as is go , as a directed acyclic graph ( dag ) . if the terms are represented by vertices and the relationships between terms are represented by edges , the terms in a dag
we used dag - edit ( 20 ) to input , manage and update syno ( figure 1 ) .
we annotated each term with name , synonyms , definition and source references , as well as the  part - of or  is - a relationship to other terms . in the definition field , we recorded additional protein keywords associated with the term as well as interpro ( 21 ) domains related to the term ( see details below in  association of proteins ) .
syno is available for download in the open biomedical ontologies flat file format ( 20 ) at .
dag - edit view of synapse ontology ( syno ) : syno is stored and managed in dag - edit .   hierarchical display of names and relationships of syno terms ;   the term of interest ;   description of the term and list of keywords and domains associated with the term and sources from which term was derived ;   synonyms of the term ;   the path from root to the term .
we developed a perl script to generate a list of search keywords based on syno , including and expanding from syno terms and synonyms .
if a syno term consists of more than one word , the perl script specified which word can be expanded and whether the order of the words can be flexible .
we searched the interpro database using the search keywords and retrieved 400 protein domains . through careful manual screening we identified 109 domains as being involved in synaptic activities and assigned them to the most appropriate syno terms .
we retrieved over 5000 proteins using the mapping between interpro and uniprot ( 22 ) and associated these proteins with syno terms .
we then searched uniprot to retrieve additional protein entries that contain the search keywords . while domain - based searches tend to have a high false - negative rate ( as not all domains can be modeled ) , keyword - based searches tend to have a high false - positive rate , requiring that we impose both automated and manual quality control .
for example , entries containing  immune or  immunological were removed , because  immunological synapse is a term defining a process in the immunological system that occurs in hundreds of protein entries . in another example , thousands of false - positive entries were removed because they were annotated as being submitted by a company named synapse . after manual review of thousands of entries , we retrieved over 10 000 proteins and assigned them with syno .
we combined the two sets of proteins and removed redundant entries following the strategy of international protein index ( 23 ) .
we considered two uniprot proteins in a species redundant if they were  95% identical over  95% of the length of the shorter sequence , based on pair - wise blastp of all sequences in the species . among redundant proteins we selected swissprot sequences over trembl sequences .
for those sequences from the same data source , we selected longer sequences over shorter ones .
the resulting syndb contains 14 000 non - redundant proteins , including 3000 in human and is the most comprehensive collection of synapse - related proteins to date .
to enhance syndb 's utility as an information resource , we developed parsers in perl to retrieve extensive information on protein sequences , expression , protein  protein and protein - small molecule interactions , disease associations and literature references .
known 3d structures or potential structure templates were retrieved by pair - wise blastp comparison between syndb proteins and non - redundant proteins with known structures from pdb_select_25 ( 24 ) .
potential metabolic pathways involved were identified by running the kobas system against the kegg database ( 26,27 ) .
the information for each protein is integrated and presented in a single graphical web page .
for example , the syndb entry page for huntingtin interacting protein 1 ( hip1 ) ( figure 2 and ) shows that hip1 is located on chromosome 7 , highly expressed in brain and involved in the huntington disease pathway .
it is included in the online mendelian inheritance in men database ( 28 ) as providing an important molecular link between huntingtin and the neuronal cytoskeleton and has sequence available for download .
a part of protein entry page for human huntingtin interacting protein 1 ( hip1 ) .
see  annotations and web interface design for a brief description and   for detail .
syndb protein annotations and cross - referenced molecular databases we implemented six interactive browsing options in syndb .
they can zoom in on a particular branch of the ontology by clicking on the 
for example , a user interested in  transmitters release and endocytosis may expand this category and focus on  synaptic vesicle cycling ( figure 3 ) . 
protein domains were grouped into interpro domain family groups which could be expanded by clicking on the group name . for each domain , the numbers of total , human , mouse and rat proteins are shown .
expand link shows all species that contain the domain and its prevalence in each . to further facilitate study of the evolution of the synapse proteome across different species , we clustered all syndb proteins by sequence similarity ( blast e - value cutoff e ) using tribe - mcl ( 29 ) and made the clusters available in the  mcl cluster browser . a separate  species browser lists all species represented in syndb , in order of decreasing number of proteins .
finally , the  chromosomal location browser ( figure 4 ) , available for human , mouse and rat , allows users to cursor over or click on chromosomal locations to see gene details .
because a number of neural gene families , such as olfactory receptors , have been known to form gene clusters along chromosomes ( 30 ) , we implemented a 
chromosomal location browser that allows the user to enter a cutoff number and view gene clusters of at least that size along a chromosome .
two loci are considered to belong to a cluster if their intergenic distance is less than 500 kb ( 30,31 ) .
chromosomal browser of syndb : the chromosomal browser is available for human , mouse and rat . the x - axis shows the different human chromosomes
+  to view a protein translated from the gene locating in that loci of the chromosome .
locus number to view gene clusters with as few as that members . from this figure
, user can get the information which chromosome and which region of the chromosome derives more synapse - related genes .
information in syndb is stored in a mysql relational database comprised of over 100 tables .
sequences can be downloaded directly from the web and the complete database is available from the authors .
we will keep syno up - to - date by regular review of the latest literature as well as users ' and collaborators ' comments .
we used the perl scripts which will automatically update the sequences in syndb followed by manual review .
the brain is a complex and subtle network of neurons that communicate with each other via synapses .
chemical synapses are asymmetric contact and play key roles in information processing and storage , behavior and disease . in order to better organize the wealth of synapse - related information and facilitate understanding of synapses
syndb aims to enable systematic studies of the synaptic functions and structures at proteomic level .
a focused ontology is essential for the development of such a database because of the numerous and diverse proteins involved . beyond general - purposed ontologies such as mesh and go ( 18,19 ) ,
focused ontologies such as syno are important because they can provide more specific , complete and resolved information to scientists , such as neuroscientists interested in synaptic function .
in fact , of 177 syno terms , only 24 were derived from mesh and go . in its first year
online , syndb has had over 600 000 external hits ( excluding search engine crawlers ) .
syndb 's objective is to serve as a repository for current knowledge and a potential starting point for experimental design or in silico data mining .
 a synapse is the junction across which a nerve impulse passes from an axon terminal to a neuron , muscle cell or gland cell . the functions and building molecules of the synapse are essential to almost all neurobiological processes . 
 to describe synaptic structures and functions , we have developed synapse ontology ( syno ) , a hierarchical representation that includes 177 terms with hundreds of synonyms and branches up to eight levels deep . 
 associated 125 additional protein keywords and 109 interpro domains with these syno terms . using a combination of automated keyword searches , domain searches and manual curation , we collected 14 000 non - redundant synapse - related proteins , including 3000 in human . 
 we extensively annotated the proteins with information about sequence , structure , function , expression , pathways , interactions and disease associations and with hyperlinks to external databases . 
 the data are stored and presented in the synapse protein database ( syndb , ) . 
 syndb can be interactively browsed by syno , gene ontology ( go ) , domain families , species , chromosomal locations or tribe - mcl clusters . 
 it can also be searched by text ( including boolean operators ) or by sequence similarity . 
 syndb is the most comprehensive database to date for synaptic proteins . 
INTRODUCTION
CONSTRUCTION OF SYNAPSE ONTOLOGY
ASSOCIATION OF PROTEINS
ANNOTATIONS AND WEB INTERFACE DESIGN
DISCUSSION