Venue: Centre Broca
Defense in english
Meera Chandra
IINS
Supervisor: Eric Hosy
Title
Nanoscale organization and plasticity-dependent remodeling of glutamate receptors in striatal synapses and its implications in Shank3- associated ASD
Abstract
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by deficits in social communication, repetitive behaviours, and restricted interests. Large-scale exome and genome sequencing have converged with high confidence to identify risk genes that encode proteins associated with synaptic assembly, maturation, and functions. Among the most prominent are scaffolding proteins of the Shank family (Shank1-3), neuroligins, neurexins, and SYNGAP1. These genes regulate the nanoscale architecture of excitatory postsynapses by anchoring glutamate receptors, controlling actin dynamics, and influencing overall synaptic transmission. Shank3 is a highly penetrant monogenic cause of ASD. Despite strong genetic and behavioural evidence, the direct understanding of nanoscale-level alterations in Shank3-haploinsufficiency remain incompletely understood. On the other hand, while AMPA-R nanodomain organisation has been observed in the hippocampus, it has not been systematically examined in the striatum.
This thesis investigates region-specific differences in AMPA-R nanoscale clustering between the hippocampus and striatum and characterized the consequences of Shank3 deficiency in these two brain regions, which are critically implicated in ASD behavioural phenotypes.
We found that AMPA-Rs display distinct nanodomain organization in hippocampal versus striatal synapses. The differential expression of Shank family proteins in the hippocampus and striatum regulates the dependency of synapses on Shank3 for the organization and anchoring of receptors. Shank3 deficiency caused more pronounced surface alterations in AMPA-R levels in the hippocampus but had subtler effects on nanodomain structure in the striatum. Nevertheless, electrophysiological studies have revealed robust deficits in AMPA-R-mediated synaptic transmission in Shank3-KO mice. Complete Shank3 deletion also led to upregulation of the surface expression of NMDA-R in dendritic spines in both brain regions. Finally, Shank3 deletion impaired mGluR-dependent long-term depression (LTD), causing no alteration in surface AMPA-R levels upon mGluR-LTD, followed by defective LTD-induced spine loss, as revealed by super-resolution and confocal imaging. Preliminary data also revealed differential synaptic responses to inflammatory cues in Shank3 heterozygous and knockout mice.
Together, with electrophysiology, super resolution microscopy and confocal imaging, this study provides the first nanoscale characterization of AMPA-R organization in the striatum and establishes a mechanistic link between Shank3 deficiency and region-specific iGluR clustering dysregulation and plasticity deficits. These findings offer new insights into well-established LTD-mechanisms using super-resolution imaging combined with the pathophysiology of ASD.
Key words : Autism, Shank3, Nanoscale organization, AMPA-R, Long term depression, Striatum
Jury
- Cécile Charrier (ENS Paris)
- Julie Perroy (IGF, Montpellier)
- Laurent Venance (CIRB, College de France, Paris)
- Jérôme Baufreton (IMN, Bordeaux)