Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses

Area of Science:

• Neuroscience
• Cell Biology
• Synaptic Plasticity

Background:

• Dystroglycan (DG) is vital for muscle integrity and neuromuscular junctions.
• DG is also found in the central nervous system and is implicated in cognitive deficits and epilepsy when mutated.
• Its role in inhibitory synapses is not well understood.

Purpose of the Study:

• To investigate the role of Dystroglycan (DG) in the homeostatic regulation of inhibitory synapses in the hippocampus.
• To determine if DG expression and function are modulated by neuronal activity.
• To elucidate the molecular mechanisms underlying DG's involvement in synaptic plasticity.

Main Methods:

• Studied activity-dependent regulation of DG expression and localization in hippocampal neurons.
• Utilized RNA interference (RNAi) to knock down DG and LARGE (like-acetylglucosaminyltransferase).
• Assessed the impact of DG modulation on GABAergic and glutamatergic synaptic transmission using electrophysiology.
• Investigated the effect of agrin on GABAergic synaptic strength.

Main Results:

• Prolonged neuronal activity increases DG expression, glycosylation, and synaptic localization.
• Inhibition of protein synthesis blocks activity-dependent increases in DG, GABAARs, and synaptic strength.
• Knockdown of DG or LARGE prevents homeostatic scaling up of inhibitory synapses.
• DG is not required for scaling down of excitatory or inhibitory synapses.
• Agrin binding to DG mimics homeostatic scaling up, suggesting a key role in GABAAR trafficking.

Conclusions:

• Dystroglycan (DG) is physiologically regulated in neurons in response to activity.
• DG and its glycosylation are essential for homeostatic plasticity at inhibitory synapses.
• Dysregulation of DG may contribute to neurological disorders associated with synaptic dysfunction.