Skip to main content

Synaptic Dysfunction in Neuropsychiatric Disorders

Periodic Reporting for period 1 - Syn2Psy (Synaptic Dysfunction in Neuropsychiatric Disorders)

Reporting period: 2019-03-01 to 2021-02-28

The large public health burden and individual suffering associated with mental disorders speaks to the need to study their biological underpinning. Genetic research, animal models of disease and human neuroimaging studies have provided convergent evidence to common pathways implicated in their aetiology, namely pathways that regulate synapse development and plasticity, which result in abnormal structural and functional connectivity in the brain of neuropsychiatric patients. The time has come to integrate studies across different levels, leading to the identification of signatures of illness associated to specific risk pathways, which can drive the development of novel therapies.
The objective of Syn2Psy is to provide high-level Ph.D. training for 14 early stage researchers (ESRs) to answer three critical questions: 1) What are the synaptic defects at the basis of neuropsychiatric disorders? 2) Which are the neuronal circuits that are disrupted, and may be targets for therapies? 3) How and when can we modulate the course of disease? Syn2Psy combines strong scientific with complementary know-how from the non-academic sector, and network-wide actions on scientific and complementary soft skills, to train a new generation of high achieving ESRs and provide them with the transferable skills necessary for thriving careers in a flourishing area. Industrial partners Lundbeck, Eurotrials and ZEISS provide experience on drug, clinical trials and technology development, the Coimbra University Hospital will expose the students to clinical research, while the clinic for child development PIN and the Marionet theatre company offer training in societal awareness and outreach. The excellent basic scientific knowledge and diverse skills acquired by ESRs will enhance their employment prospects in both the academic and non-academic sectors, and their scientific contributions will inform novel therapeutic approaches for alleviating this leading cause of disability worldwide.
During the first reporting period, Syn2Psy Early Stage Researchers have conducted experiments to characterize new genetic models of Intellectual Disability, Schizophrenia and Autism Spectrum Disorder (ASD), at the neurophysiological, morphological and behavioural levels. For this, models built based on human genetic data and on the implication of the candidate proteins in crucial pathophysiological pathways are being used. Studies are being conducted to establish the role of Stargazin in psychiatric disorders; to identify the role of specific mitochondrial genes in the development of psychopathologies and to develop and characterize human-derived neurons and brain organoids as models of neurodevelopmental disorders.
To dissect nanostructural changes in synapse dynamics in models of neuropsychiatric disorders and to explore the mechanisms underlying excitation/inhibition (E/I) imbalance in models of neuropsychiatric disease and to monitor E/I balance at the population level, Syn2Psy ESRs are focusing on the identification of the link between synaptic nanoscale alterations and behavioural defects in animal and human models of Shank3-related Autism Spectrum Disorder (ASD); on the characterization of cortical E/I imbalance in vivo in models of synaptic dysfunction using mesoscopic methods; on the identification of defects in single N-methyl-D-aspartate (NMDA) receptor dynamics in Psychosis; on the identification of presynaptic defects and alterations in glutamate receptor dynamics in Fragile X Syndrome (FXS); on the depiction of synapses and functional networks in a new paradigm to model Down’s Syndrome (DS); and on the characterization of the synaptic and neural correlates of spatial memory deficits in a glycine receptor knockout model of ASD.
Finally, Syn2Psy ESRs are focusing on the study of the therapeutic potential of the endocannabinoid system in an Autism Spectrum Disorder (ASD) model; on the identification of aberrant synaptic mRNA translation as a point of convergence for multiple genetic causes of ASD/ID; on the establishment of the impact of the corticotropic releasing hormone system on Schizophrenia (SCZ)- and ASD- related endophenotype; on the identification of circuit deficits associated with ASD; as well as on the identification of the role of the excitation/ inhibition (E/I) imbalance in the corticothalamic system in the development of neuropsychiatric disorders.
Until the end of the project, Syn2Psy aims to inform better therapeutic strategies, to configure a new mindset for the research community devoted to the investigation of neuropsychiatric disorders, and to adequately prepare the next generation of researchers in the field.