Contrastsing synaptic roles of MDGA1 and MDGA2

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Neurodevelopmental disorders often stem from mutations in synaptic organizing molecules.
• MDGA1 and MDGA2 are synaptic organizers with debated roles as synaptic repressors.
• Conflicting evidence exists regarding the precise localization of MDGAs at synapses.

Approach:

• Utilized epitope-tagged MDGA1 and MDGA2 knock-in mice to study native protein expression and localization.
• Employed shRNA knockdown and CRISPR/Cas9 knockout strategies to investigate functional consequences of MDGA1 and MDGA2 loss.
• Examined effects on both excitatory (AMPA and NMDA receptor-mediated) and inhibitory (GABAergic) synaptic transmission.

Key Points:

• Native MDGA1 and MDGA2 proteins are broadly expressed in the brain, with peak expression during early postnatal development.
• Endogenous MDGA1 is specifically enriched at excitatory synapses.
• MDGA1 deficiency impairs AMPA receptor-mediated transmission cell-autonomously.
• MDGA2 deficiency selectively depresses NMDA receptor-mediated transmission and enhances inhibitory transmission.

Conclusions:

• MDGA2 functions as a synaptic repressor specifically at inhibitory synapses.
• Both MDGA1 and MDGA2 are essential for excitatory synaptic transmission.
• MDGA1 and MDGA2 exhibit an unprecedented, nonoverlapping division of labor, highlighting their distinct roles in synaptic function.