Following Excitation/Inhibition Ratio Homeostasis from Synapse to EEG in Monogenetic Neurodevelopmental Disorders

Abstract

Pharmacological options for neurodevelopmental disorders are limited to symptom suppressing agents that do not target underlying pathophysiological mechanisms. Studies on specific genetic disorders causing neurodevelopmental disorders have elucidated pathophysiological mechanisms to develop more rational treatments. Here, we present our concerted multi-level strategy ‘BRAINMODEL’, focusing on excitation/inhibition ratio homeostasis across different levels of neuroscientific interrogation. The aim is to develop personalized treatment strategies by linking iPSC-based models and novel EEG measurements to patient report outcome measures in individual patients. We focus our strategy on chromatin- and SNAREopathies as examples of severe genetic neurodevelopmental disorders with an unmet need for rational interventions.

Developing Gene-Based Personalised Interventions in Autism Spectrum Disorders

“…For example, the role of mutations in the mTOR or RAS signalling pathways show similar neuropathological characteristics in human and rodent models [ 16 ]. Gene expression pattern, neural synaptic function, or the imbalance of inhibitory and excitatory neural functions are other well-studied aspects which can be compared between rodent and human models [ 13 , 17 , 18 ]. Additionally, the role of somatic mutations has been the focus of recent exciting developments, especially in the field of treatment-resistant epilepsy, as documented both in humans and in animal models [ 19 , 20 ].…”

From Genes to Therapy in Autism Spectrum Disorder

“…This is the approach taken by the collaborative BRAINMODEL project, reported by Geertjens et al, which focuses on patients with specific genetic variants and subsequently aims to integrate patient-specific biomarker data obtained through different data modalities. These include in vitro synaptic (network) activity in patient-iPSC-derived neurons and electroencephalography, obtained separately in each enrolled patient with the sole objective to elucidate the best therapeutic strategy for this individual person [ 11 ].…”

“…Indeed, proposed over a decade ago [ 26 , 27 , 28 ], the biological convergence of different genetic variants on synaptic function is no longer merely theoretical. A concrete clinical implementation of this knowledge is one of the premises of the previously mentioned collaborative BRAINMODEL project which identifies one of its target groups by the presence of pathogenic variants affecting synaptic function [ 11 ]. Large-scale projects, such as EU-AIMS, follow the same rationale of stratifying individuals with ASD for clinical trials based on underlying pathophysiology [ 29 ].…”

“…Of particular interest are their emergence during the first year of life [ 45 ], and their correlation with the other autistic symptom domains [ 46 ]. These observations underscore their potential as early biomarker of ASD [ 47 ] and as clinical endpoint measure in trials, such as proposed by the BRAINMODEL project [ 11 ]. The rationale for such novel approaches is further strengthened by the observation of sensory abnormalities in mouse models of various genetic variants associated with ASD [ 20 , 30 , 48 ].…”

“…Several articles in this Special Issue describe the contribution that patient-derived iPSCs and derived neuronal models can give to our understanding of the pathophysiology of ASD, especially in reference to known genetic disorders [ 11 , 20 ]. Furthermore, being able to test the therapeutic effects of pharmacological agents in these models provides a great opportunity to bypass the limitations imposed by species-specific epigenetic control and functional responses when using primary cultures from murine models.…”