PROJECT: JTC2021: MINERVA

Microglia/neuron crosstalk in autism spectrum disorder: Role of early inflammatory activation

Abstract

Our knowledge on how microglia shape brain excitatory/inhibition (E/I) balance and whether it is disturbed by early maternal infections or genetic factors and accessible for new therapeutic interventions in autism spectrum disorders (ASD), especially in humans, remains elusive. MINERVA takes advantage of deeply phenotyped patient cohort, novel human stem cell -based models and in vivo models with sensitive behavioral readouts to investigate how maternal infection and genetic risk factors interact and drive microglia activation patterns resulting in GABAergic mediated E/I balance and neurodevelopmental disturbances. We reproduce ASD profile in human cellular and animal models to identify mechanisms and stimuli that disrupt normal neurodevelopment and accelerate the severity of resulting ASD phenotypes. MINERVA creates a basis for novel treatments correcting abnormal network maturation, targeting either abnormal GABAergic drive via KCC2 transporters, or disease immune signature. From a small cohort of ASD patients stratified, by immune signature we will bring new, clinically translatable principles of the ASD therapy amenable for large patient groups. MINERVA promotes meaningful involvement of Individuals with ASD in all steps of research including study design, conduct and dissemination to better address the clinical needs fo individuals with ASD. These activities provide feedback on challenges, ethical issues and social engagement linked to participant involvement.

Keywords

Stem cells and neural differentiation/cell therapy, Imaging techniques, Electrophisiological approaches, Behavioural methodologies, omics approaches, neurodevelopment, Patient cohorts, Animal studies, microglia, neuron, autism spectrum disorder, induced pluripotent stem cell, excitatory/inhibitory balance

Call topic

Neurodevelopmental Disorders

Proposed runtime

n/a - n/a

Project team

Tarja Malm (Coordinator)
Finland (AKA)
Markus Wöhr
Belgium (FWO)
Carsten Culmsee
Germany (BMBF)
Judith Alferink
Germany (BMBF)
Laura Ricceri
Italy (own funds)