Development and validation of translational platforms in support of synaptopathy drug discovery The overarching aim of this topic is to develop an improved understanding of the causative or contributory role of synaptic alterations in CNS disorders, which must be valid and applicable to drug discovery and development across the diverse therapeutic CNS areas. The aim is to construct a precompetitive research consortium focused on furthering our scientific understanding of how synaptopathies can elicit or contribute to brain disorders. In addition, the focus will be to develop and validate both existing and innovative translational tools and platforms to facilitate drug discovery targeting synaptic health. To achieve the overall aim of the topic, applicants should focus on at least one of the four major brain disorders namely Alzheimer’s, Parkinson’s disease, major depression and schizophrenia, and ideally at least two, one in the neurodegenerative and one in the psychiatric/neurodevelopmental field. Specifically, the effort should be divided into two key areas. Deep clinical phenotyping of CNS disorder patients to enable the development of robust tools to measure disease and treatment effects on the synapse.Characterisation of existing and development of novel preclinical synaptopathy disease models Central nervous system (CNS) disorders are some of the most prevalent, devastating and poorly treated illnesses that impact individuals, families and society. It is estimated that annually in Europe alone, approximately 38 % of the population will suffer from a CNS disorder. The term ‘synaptopathy’ is typically used to describe CNS disorders caused by synaptic deficits, irrespective of whether the alterations are primary or caused by underlying pathophysiological processes Whilst our emerging understanding of how synapses are pathologically altered in certain brain disorders is leading to innovative opportunities for drug discovery, there are considerable challenges impeding effective research that still remain. Furthermore, the current technologies and platforms employed within early drug discovery are not fully characterised with respect to their predictive translational value, thus leading to a high risk of failure once compounds are progressed into the clinic. What is desperately needed therefore is the identification and validation of robust, sensitive and translational platforms capable of quantifying synaptic alterations both preclinically and clinically. Such platforms should be fit for purpose to detect and quantify dynamically both disease and treatment effects. Finally, we need to demonstrate the value of these new tools and methods for supporting drug discovery and development efforts across a spectrum of therapeutic CNS indications, including neurodegenerative, neurodevelopmental and psychiatric disorders. The expanded knowledge base generated to define the contribution that synaptopathies play in neurodevelopmental, psychiatric and neurodegenerative disorders will lead to improved disease pathway understanding and thus better position academia, SMEs and pharmaceutical companies to identify and validate tractable drug targets. The concerted and aligned efforts will minimise duplication and redundancy. The tools, platforms and technologies will ultimately drive success in both the discovery and clinical arenas by providing robust translatable evidence of early clinical efficacy as compounds are evaluated in patient populations. These achievements will facilitate the delivery of much needed, highly effective medicines and treatments for CNS disorders.