Diagnosing and treating synaptopathies Many neurological and psychiatric disorders can be regarded as synaptopathies — i.e. diseases due to dysfunctional synapses, the junctions across which two neurons communicate. They include epilepsy, schizophrenia, neurodegenerative disorders, autism and depression. Health © Benjamin H. Cooper Mutations in genes coding for synaptic proteins are involved in the causation of neurological and psychiatric disorders, but a comprehensive understanding of the molecular processes leading to disease is still lacking. The EU-backed 'European consortium on synaptic protein networks in neurological and psychiatric diseases' (EUROSPIN) project aimed at improving understanding of the mechanisms leading to synaptopathies. A multi-level systems biology approach was used to unravel the mechanisms linking mutations in genes coding for synaptic proteins to the occurrence of neurological and/or psychiatric disorders. Such an approach relies on a wide range of disciplines and techniques, spanning from biochemistry to behavioural studies. Through an improved understanding of disease causation, the consortium delivered novel leads for diagnostic tools and therapies of synaptopathies. Scientists completed large-scale screens of protein-protein interactions (PPIs) of 1 340 synaptic proteins and generated PPI networks of 7 677 interactions. Moreover, mice lines were created that expressed tandem affinity purification-tagged synaptic proteins for several applications such as protein purification and screening of substrates. An antibody production pipeline enabled protein expression and localisation studies. In combination, these are very useful tools to study synaptic protein complexes and aberrant PPI changes in disease models. Eighteen validated mouse lines representing different synaptopathies (e.g. SNAP-25 knockout (KO) mice for attention deficit hyperactivity disorder (ADHD)) were used to analyse synaptic transmission and plasticity as well as behaviour. Additionally, cell biological and electrophysiological studies were carried out on disease-relevant synaptic proteins such as SNAP25, Munc18-1 and NLGN-2. An important finding was that antiepileptic drugs could be useful in ADHD treatment. Using behavioural analyses, neuronal circuits in fear conditioning were characterised to assess plasticity and learning in mice models. Interestingly, NLGN-2 KO mice were unable to acquire fear in response to certain stimuli due to reduced inhibitory synaptic transmission in the amygdala. Studies revealed that a subset of 1 026 synaptic genes rather than an individual gene causes schizophrenia by affecting signal transduction, synaptic excitability, cell adhesion and trans-synaptic signalling. Small molecules were synthesised that affected the aggregation of beta-amyloid peptides commonly seen in Alzheimer's disease that could prove effective in therapy. Project outcomes could now enable the synthesis of small molecules that can effectively treat synaptopathies and restore normal function. Besides placing the EU ahead in the biomedical sector, project outcomes will improve patients' quality of life while reducing the socioeconomic burdens caused by synaptopathies. Keywords Synaptopathies, neurological, psychiatric, synapses, synaptic protein networks
