Periodic Reporting for period 2 - Syn2Psy (Synaptic Dysfunction in Neuropsychiatric Disorders)
Okres sprawozdawczy: 2021-03-01 do 2023-08-31
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. Syn2Psy aimed 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.
Syn2Psy provided 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 combined strong scientific evidence 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 this flourishing area.
Syn2Psy provided 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 combined strong scientific evidence 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 this flourishing area.
ESR1 generated a knock-in mouse model carrying a variant of Stargazin identified in a patient suffering from schizophrenia and showed that genetic susceptibility, as conferred by the stargazin variant, generates alterations in synaptic function and dendritic spine morphology, as well as produces cognitive behavioural phenotypes characteristic of schizophrenia in a mouse model.
ESR2 dissected the participation of GTPase mitofusin 2 (Mfn2) in mitochondrial, morphological and synaptic alterations in the nucleus accumbens (NAc) medium spiny neurons (MSNs) expressing dopamine receptor 1 in mice, as well as its impact on effort-related behaviour. The obtained results report for the first time that decreased Mfn2 levels have a causal role in cellular alterations in this neuronal subpopulation and in deficits of motivated behaviour.
ESR3 used cellular reprogramming, electrophysiology and imaging work to conduct a study which involved the chronic exposure of brain organoids, derived from human-induced pluripotent stem cells, to valproic acid (VPA). Findings suggest a potential impact of VPA on individual neurons and neuronal network hyperexcitability in organoids exposed to VPA, indicating an excitatory/inhibitory imbalance. This research will help better understand what are the common hallmarks leading to neurodevelopmental disorders.
ESR5 generated neurons from control donors and developed both an in vitro and in vivo system for the characterisation of the short and long-term effects of psychedelic drugs on human cortical wiring.
ESR6 examined the synaptic disturbance induced by indirect actions of both NMDAR- and GABAaR-autoantibodies, encompassing dysfunction at excitatory and inhibitory inputs to hippocampal cells. Further, ESR6 has broadened the model of disease pathogenesis to include the altered functionality of GABAergic interneurons in hippocampal networks.
ESR7 dissected the contribution of fragile X messenger ribonucleoprotein (FMRP) - an RNA binding protein involved in the trafficking and translational control of a wide variety of mRNAs - in maintaining a proper balance of the physiology of the synapse and described several pre- and postsynaptic proteins that are dysregulated upon Fmr1 knock-out or knock-down.
ESR8 investigated the mechanisms behind the cellular and synaptic alterations observed after transplanting induced pluripotent stem cell (iPSC)-derived neurons from Down syndrome donors and matched controls. The results suggested that trisomy 21-related dysregulation is not sufficient to alter axonal bouton stability and neuronal activity when compared to control neural networks of similar scale and cellular composition.
ESR9 investigated the cellular and functional alterations underlying the cognitive deficits observed in mice lacking Glra2, a gene encoding the glycine receptor alpha 2 subunit and recently implicated in autism spectrum disorder and intellectual disability. The results pointed to excitatory hyperconnectivity and excitatory/inhibitory imbalance in the prefrontal cortex. Loss of Glra2 also resulted in hypoactivation of the prefrontal cortex and aberrant glutamatergic response during object recognition, implicating alpha 2-mediated glycinergic signalling in normal prefrontal circuit assembly and function.
ESR10 studied the effects of the modulation of the endocannabinoid system on the phenotype of Shank3-deficient mouse, a model of autism and Phelan-McDermid syndrome (PMS). This work represents the first attempt to specifically modulate cannabinoid type 1 (CB1) receptor activity in Shank3-deficient mice and proposes it as a new pharmacological target for PMS. Based on the therapeutic profile of one of the compounds studied, the results describe a novel pharmacological candidate for the treatment of PMS and, more generally, of autism.
ESR11 studied how pharmacological modulation of small conductance Ca2+-activated K+ (SK) channels affects neuronal firing and intrinsic properties in the thalamic reticular nucleus (TRN). Results showed that SK channel modulators affect the firing pattern and frequency in TRN neurons, which suggests that SK channel allosteric modulators, are useful tools for modulating thalamic reticular nucleus activity.
ESR12 explored the translation fraction in two models of autism, Fragile X Syndrome and Syngap Haploinsufficiency, and showed that Fmr1-/y and Syngap+/- models have different mechanisms of regulation, despite convergent regulation of processes such as translation and DNA transcription.
ESR13 investigated the neuromodulation of NREM sleep by the stress-related corticotropin-releasing hormone (CRH) through the activation of its receptor in the thalamic reticular nucleus (TRN). The results indicate that CRH may act as a limiting factor in the generation of NREM sleep spindles by modulating the excitability of TRN neurons.
ESR14 studied two rat lines of SYNGAP1 haploinsufficiency and observed reduced social interaction and general lack of interrest provides valuable insights into the underlying mechanisms of social behaviour deficits observed in individuals with SYNGAP1 mutations.
ESR2 dissected the participation of GTPase mitofusin 2 (Mfn2) in mitochondrial, morphological and synaptic alterations in the nucleus accumbens (NAc) medium spiny neurons (MSNs) expressing dopamine receptor 1 in mice, as well as its impact on effort-related behaviour. The obtained results report for the first time that decreased Mfn2 levels have a causal role in cellular alterations in this neuronal subpopulation and in deficits of motivated behaviour.
ESR3 used cellular reprogramming, electrophysiology and imaging work to conduct a study which involved the chronic exposure of brain organoids, derived from human-induced pluripotent stem cells, to valproic acid (VPA). Findings suggest a potential impact of VPA on individual neurons and neuronal network hyperexcitability in organoids exposed to VPA, indicating an excitatory/inhibitory imbalance. This research will help better understand what are the common hallmarks leading to neurodevelopmental disorders.
ESR5 generated neurons from control donors and developed both an in vitro and in vivo system for the characterisation of the short and long-term effects of psychedelic drugs on human cortical wiring.
ESR6 examined the synaptic disturbance induced by indirect actions of both NMDAR- and GABAaR-autoantibodies, encompassing dysfunction at excitatory and inhibitory inputs to hippocampal cells. Further, ESR6 has broadened the model of disease pathogenesis to include the altered functionality of GABAergic interneurons in hippocampal networks.
ESR7 dissected the contribution of fragile X messenger ribonucleoprotein (FMRP) - an RNA binding protein involved in the trafficking and translational control of a wide variety of mRNAs - in maintaining a proper balance of the physiology of the synapse and described several pre- and postsynaptic proteins that are dysregulated upon Fmr1 knock-out or knock-down.
ESR8 investigated the mechanisms behind the cellular and synaptic alterations observed after transplanting induced pluripotent stem cell (iPSC)-derived neurons from Down syndrome donors and matched controls. The results suggested that trisomy 21-related dysregulation is not sufficient to alter axonal bouton stability and neuronal activity when compared to control neural networks of similar scale and cellular composition.
ESR9 investigated the cellular and functional alterations underlying the cognitive deficits observed in mice lacking Glra2, a gene encoding the glycine receptor alpha 2 subunit and recently implicated in autism spectrum disorder and intellectual disability. The results pointed to excitatory hyperconnectivity and excitatory/inhibitory imbalance in the prefrontal cortex. Loss of Glra2 also resulted in hypoactivation of the prefrontal cortex and aberrant glutamatergic response during object recognition, implicating alpha 2-mediated glycinergic signalling in normal prefrontal circuit assembly and function.
ESR10 studied the effects of the modulation of the endocannabinoid system on the phenotype of Shank3-deficient mouse, a model of autism and Phelan-McDermid syndrome (PMS). This work represents the first attempt to specifically modulate cannabinoid type 1 (CB1) receptor activity in Shank3-deficient mice and proposes it as a new pharmacological target for PMS. Based on the therapeutic profile of one of the compounds studied, the results describe a novel pharmacological candidate for the treatment of PMS and, more generally, of autism.
ESR11 studied how pharmacological modulation of small conductance Ca2+-activated K+ (SK) channels affects neuronal firing and intrinsic properties in the thalamic reticular nucleus (TRN). Results showed that SK channel modulators affect the firing pattern and frequency in TRN neurons, which suggests that SK channel allosteric modulators, are useful tools for modulating thalamic reticular nucleus activity.
ESR12 explored the translation fraction in two models of autism, Fragile X Syndrome and Syngap Haploinsufficiency, and showed that Fmr1-/y and Syngap+/- models have different mechanisms of regulation, despite convergent regulation of processes such as translation and DNA transcription.
ESR13 investigated the neuromodulation of NREM sleep by the stress-related corticotropin-releasing hormone (CRH) through the activation of its receptor in the thalamic reticular nucleus (TRN). The results indicate that CRH may act as a limiting factor in the generation of NREM sleep spindles by modulating the excitability of TRN neurons.
ESR14 studied two rat lines of SYNGAP1 haploinsufficiency and observed reduced social interaction and general lack of interrest provides valuable insights into the underlying mechanisms of social behaviour deficits observed in individuals with SYNGAP1 mutations.
- Development of new models for Schizophrenia and ASD;
- New knowledge on motivational disorders, FXS, DS, ASD, ID and SYNGAP1 haploinsufficiency, as well as on the effects of psychedelics on human cortical circuit dynamics and on the implications of NMDA and GABAA receptor autoantibodies for seizures, cognitive dysfunction, and synaptic plasticity;
- Potential development of novel therapeutic strategies for depression, ASD, ID and FXS;
- Novel pharmacological candidate for the treatment of PMS and ASD;
- Potential new biomarkers that could contribute to the identification of individuals at risk for developing sleep impairments or psychiatric disorders in clinical studies;
- Potential development of therapeutic strategies for treating disorders involving thalamic reticular dysfunction;
- Potential identification of novel target for the treatment of stress or anxiety-induced sleep impairments;
- Potential design of interventions for SYNGAP1 haploinsufficiency.
- New knowledge on motivational disorders, FXS, DS, ASD, ID and SYNGAP1 haploinsufficiency, as well as on the effects of psychedelics on human cortical circuit dynamics and on the implications of NMDA and GABAA receptor autoantibodies for seizures, cognitive dysfunction, and synaptic plasticity;
- Potential development of novel therapeutic strategies for depression, ASD, ID and FXS;
- Novel pharmacological candidate for the treatment of PMS and ASD;
- Potential new biomarkers that could contribute to the identification of individuals at risk for developing sleep impairments or psychiatric disorders in clinical studies;
- Potential development of therapeutic strategies for treating disorders involving thalamic reticular dysfunction;
- Potential identification of novel target for the treatment of stress or anxiety-induced sleep impairments;
- Potential design of interventions for SYNGAP1 haploinsufficiency.