PROJECT: JTC2021 - Neurodevelopmental Disorders: SHANKAstro

Astrocytes dysfunctions in Phelan McDermid syndrome: from mechanisms towards new therapeutic strategies


The lack of one copy of the Shank3 gene is the main cause of the neuropsychiatric symptoms of Phelan McDermid syndrome (PMS), a neurodevelopmental disorder characterised by intellectual disability and autistic-like deficits. To date, Shank3-related syndromes have only been investigated from a neuronal perspective, but recent data have highlighted a possible involvement of astrocytic Shank3 in the pathophysiology of PMS. Astrocyte-specific deletion of Shank3, early in post-natal development, has an impact on mGluR5 activity, a main signalling pathway during post-natal astrocyte development. This is associated with impaired astrocyte maturation and recapitulates many of the main phenotypes of PMS mouse models, such as impaired synaptogenesis, repetitive behaviours and cognitive dysfunction. These findings suggest that defects in the post-natal maturation of Shank3 mutant astrocytes may (at least partially) account for the neuronal dysmorphogenesis, synaptopathies, and behavioural impairments associated with Shank3-related syndromes. By deleting and re-expressing astrocyte-specific Shank3 in systems ranging from in vitro cultures to state-of-the-art animal models and next-generation patient-derived brain organoids, we will be able to provide important new insights into the pathological mechanisms of neurodevelopment in PMS. These could guide development of therapies for PMS, and possibly other autism-spectrum disorders characterised by mGluR5 signalling dysfunction.


Electrophisiological approaches, Stem cells and neural differentiation/cell therapy, Animal studies, astrocytes

Call topic

Neurodevelopmental Disorders

Proposed runtime

n/a - n/a

Project team

Joao Peca (Coordinator)
Portugal (FCT)
Paola Bezzi
Switzerland (SNSF)
Davide Ragozzino
Italy (MOH)
Tobias Boeckers
Germany (BMBF)
Lutgarde Arckens
Belgium (FWO)

Lay summary