AUTHOR=Jeckel Pauline , Kriebel Martin , Volkmer Hansjürgen 

TITLE=Autism Spectrum Disorder Risk Factor Met Regulates the Organization of Inhibitory Synapses

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=14

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2021.659856

DOI=10.3389/fnmol.2021.659856

ISSN=1662-5099

ABSTRACT=<p>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 <italic>in vivo</italic> and <italic>in vitro</italic> that Met is necessary and sufficient for the stabilization of GABAergic synapses <italic>via</italic> induction of gephyrin clustering. Likewise, we provide evidence for Met-dependent gephyrin clustering <italic>via</italic> activation of mTOR. Our results support the notion that deficient GABAergic signaling represents a pathomechanism for ASD.</p>