Abstract
A common hypothesis explains autism spectrum disorder (ASD) as a neurodevelopmental disorder linked to excitatory/inhibitory (E/I) imbalance in neuronal network connectivity. Mutation of genes including Met and downstream signaling components, e.g., PTEN, Tsc2 and, Rheb are involved in the control of synapse formation and stabilization and were all considered as risk genes for ASD. While the impact of Met on glutamatergic synapses was widely appreciated, its contribution to the stability of inhibitory, GABAergic synapses is poorly understood. The stabilization of GABAergic synapses depends on clustering of the postsynaptic scaffolding protein gephyrin. Here, we show in vivo and in vitro that Met is necessary and sufficient for the stabilization of GABAergic synapses via induction of gephyrin clustering. Likewise, we provide evidence for Met-dependent gephyrin clustering via activation of mTOR. Our results support the notion that deficient GABAergic signaling represents a pathomechanism for ASD.
Highlights
Autism spectrum disorder (ASD) is a highly heterogeneous disease affecting ∼2% of the population (Sharma et al, 2018)
Our results imply a function of Met in the regulation of gephyrin clustering through mTOR signaling
Our report clarifies the role of inhibitory synapse stabilization by the autism spectrum disorder (ASD) risk genes Met and Tsc2 at the morphological level
Summary
Autism spectrum disorder (ASD) is a highly heterogeneous disease affecting ∼2% of the population (Sharma et al, 2018). The association with developmental deficits as a major cause qualified ASD as a neurodevelopmental disorder (Sahin and Sur, 2015). In this line, aberrant neurodevelopment in ASD was suggested to provoke an excitatory/inhibitory (E/I) imbalance of synaptic connectivity as an underlying pathomechanism (Nelson and Valakh, 2015). E/I imbalance may be caused by deregulated expression or mutation of genes linked to excitatory and inhibitory synapse formation or stabilization. MET was identified as an ASD risk gene involved in synapse formation. Met mutation in the developing rodent nervous system is linked to impaired dendritic complexity, spine morphology and, glutamatergic synapse formation (Qiu et al, 2014).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
