Discover the groundbreaking database illuminating the intricate social network of our synapses
Explore the ScienceImagine a city with 2,160 different types of specialists, all working in a space one-millionth the size of a pinhead, communicating through precisely coordinated handshakes that can reshape their organization in seconds.
This isn't science fiction—this is the postsynaptic density, the complex receiving station of our brain cells where learning, memory, and cognition emerge from molecular interactions. For decades, neuroscientists struggled to map this intricate network, with data scattered across thousands of scientific papers or buried in generic databases not designed to capture the unique features of synaptic proteins.
Enter PSINDB, the Postsynaptic Interaction Database—a groundbreaking digital resource that's illuminating the molecular social network of our synapses with unprecedented clarity. Developed by researchers at Pázmány Péter Catholic University, this freely available database represents the most comprehensive collection of human postsynaptic protein-protein interactions ever assembled, offering scientists worldwide a powerful tool to understand how our brains work at the most fundamental level—and what happens when things go wrong in neurological and psychiatric disorders 1 2 .
Understanding the molecular machinery behind learning and memory
The postsynaptic region is the receiving end of brain communication, a sophisticated molecular machine that processes chemical signals from neighboring neurons. This intricate structure, particularly in excitatory neurons, contains a specialized formation called the postsynaptic density (PSD)—a dense network of proteins directly beneath the cell membrane that forms and strengthens synaptic connections through precise protein interactions 2 .
PSINDB has defined the human postsynaptic proteome by integrating data from four established resources: GeneOntology, SynGO, SynaptomeDB, and Gene2Cognition. This integration identified 2,160 proteins that constitute the postsynaptic machinery, though only 5.4% of these appeared in all source databases, highlighting both the complexity and the specialization of different research approaches 2 .
Within the postsynaptic density, proteins don't operate in isolation—they form an elaborate, dynamically changing network where interactions are constantly forming, breaking, and reorganizing. This molecular dance isn't random; it follows specific rules and patterns that PSINDB meticulously documents 2 .
These protein-protein interactions (PPIs) are fundamental to synaptic plasticity—the ability of synapses to strengthen or weaken over time—which is considered the cellular basis for learning and memory. The postsynaptic network is remarkably complex: of the 2,160 postsynaptic proteins, 54.5% have between 1-50 interacting partners, while 475 proteins (22%) can bind to more than 100 different partners, creating an incredibly dense interaction landscape 2 .
Total PS Proteins
Proteins with 1-50 Partners
54.5%Proteins with >100 Partners
22%Proteins in All Databases
5.4%Interactive network visualization would appear here in a live implementation
Hover over nodes to see protein details and connection information
While other protein interaction databases exist, PSINDB stands out as a specialized resource specifically designed to capture the unique aspects of postsynaptic function. It brings together experimental and computational evidence about interactions, along with structural and disease-related information, creating a multidimensional view of the postsynaptic world that generic databases simply can't provide 1 .
The database includes manually curated information from nearly 2,000 experiments collected from scientific literature, complemented by data from IntAct, BioGRID, Protein Data Bank, and high-confidence computational predictions from the STRING database. This comprehensive approach ensures researchers can access both established and emerging knowledge about synaptic interactions 2 3 .
PSINDB offers sophisticated visualization tools that allow researchers to explore proteins and their interactions in intuitive ways. The database provides detailed information about precise binding regions—the exact locations where proteins interact—classified by different levels of evidence from "binding-associated regions" to "atomic contacts" derived from structural data 2 .
Perhaps most importantly, PSINDB captures the regulatory mechanisms that control synaptic interactions, including post-translational modifications and alternative splicing. These mechanisms act as molecular switches that can turn interactions on or off, with more than 50% of the postsynaptic proteome containing phosphorylation sites and approximately one-third using alternative splicing to regulate interactions 2 .
| Regulatory Mechanism | Prevalence in PS Proteome | Primary Function |
|---|---|---|
| Phosphorylation sites | >50% | Acts as molecular switches by adding phosphate groups |
| Alternative splicing | ~33% | Creates different protein versions from the same gene |
| Competitive binding | ~33% | Multiple partners competing for the same binding site |
| Combined use of 4+ mechanisms | ~10% | Complex multi-layer regulation |
To understand how PSINDB advances research, consider its work on the shisa family of proteins—specifically shisa-6 and shisa-7. These single-pass transmembrane receptors are known to regulate transmission in CA3-CA1 synapses in the hippocampus, a brain region crucial for memory formation. They function by regulating AMPA-type glutamate receptors, which are essential for fast synaptic signaling 2 .
Before PSINDB's manual curation efforts, the known interaction networks for both shisa-6 and shisa-7 were limited, restricting scientists' understanding of their full functional capabilities. By systematically reviewing the scientific literature, the PSINDB team significantly expanded these networks, adding 8 new interactions for shisa-6 and 11 for shisa-7. This expansion revealed previously unknown connectivity patterns and suggested new functional roles for these receptors in synaptic organization 2 .
The PSINDB team employed rigorous manual curation of scientific literature, focusing on papers that might have been missed by generic databases. They followed standardized community curation processes and data interpretation to ensure interoperability with other resources. Each interaction was annotated with detailed experimental information, including the interaction detection method, host organism, and the biological role of participants 2 3 .
For binding region information, the team used a structured classification system based on HUPO-PSI Molecular Interaction ontology terms, distinguishing between "binding-associated regions," "sufficient for binding," and "necessary for binding." This precision allows researchers to understand not just whether two proteins interact, but exactly how and where they connect at the molecular level 2 .
Total: 20 interactions
Total: 31 interactions
Advanced techniques for visualizing molecular interactions in the brain
Studying protein-protein interactions in synapses requires sophisticated methodologies that can capture these transient, precise molecular handshakes. Researchers have developed multiple approaches, each with unique strengths for visualizing different aspects of synaptic interactions 4 .
| Method Category | Specific Techniques | Primary Applications and Functions |
|---|---|---|
| Structural Biology | X-ray Crystallography, NMR Spectroscopy | Determines high-resolution 3D structures of protein complexes; reveals atomic-level interaction details |
| Biophysical Analysis | Surface Plasmon Resonance (SPR), Isothermal Titration Calorimetry (ITC) | Measures binding kinetics, affinity, and thermodynamic parameters |
| Cellular Interaction Assays | Synaptosome-based FlowPLA (Syn-FlowPLA), Proximity Ligation Assay | Detects endogenous protein interactions in near-native environments; maps interaction networks in functional synapses |
| Computational Approaches | Molecular Docking, Principal Component Analysis, Elastic Network Models | Predicts binding modes and affinities; extracts dynamic information from experimental structures |
One particularly innovative method for studying human synaptic interactions is Syn-FlowPLA, which combines synaptosome isolation with flow cytometry proximity ligation assay. This approach allows researchers to detect protein-protein interactions within the native synaptic environment, even using frozen human brain tissues 4 .
The method involves isolating synaptosomes—detached-and-resealed synaptic terminals that retain both pre- and postsynaptic components—from cryopreserved human brain tissues. These synaptosomes are then gently fixed and incubated with primary antibodies against the proteins of interest. Specialized PLA probes with attached oligonucleotides are added, which generate a fluorescent signal only if the two target proteins are within 40 nanometers of each other—close enough to interact. This signal is then detected and quantified using flow cytometry 4 .
PSINDB represents more than just a database—it's a dynamic research platform that continues to evolve with new discoveries. As researchers worldwide contribute additional findings and the curation team continues to expand its annotations, this resource will grow increasingly comprehensive and valuable 1 2 .
The potential applications are vast, from understanding neurological and psychiatric diseases to developing targeted therapeutics. PSINDB already includes disease-associated germline mutations, with many linked to nervous system disorders like autism spectrum disorder, Alzheimer's disease, and schizophrenia.
Interestingly, the database has also revealed that mutations in postsynaptic proteins can cause heart and muscular diseases, highlighting the unexpected roles these proteins may play beyond the brain 2 .
As PSINDB continues to map the intricate social network of our synapses, it brings us closer to answering one of science's greatest mysteries: how the physical interactions of proteins give rise to the abstract world of thoughts, memories, and consciousness itself.
In the elaborate dance of synaptic proteins, we may eventually find the very steps that make us human. The database serves as both a repository of current knowledge and a springboard for future discoveries in neuroscience and beyond.
PSINDB is freely available to researchers worldwide
Visit PSINDB OnlineDatabase Access: PSINDB is freely available at https://psindb.itk.ppke.hu/ 1