Distinct mechanisms drive sequential internalization and degradation of GABARs during global ischemia and reperfusion injury.

Synaptic inhibition is critical for controlling neuronal excitability and function. During global cerebral ischemia (GCI), inhibitory synapses are rapidly eliminated, causing hyper-excitability which contributes to cell-death and the pathophysiology of disease. Sequential disassembly of inhibitory synapses begins within minutes of ischemia onset: GABARs are rapidly trafficked away from the synapse, the gephyrin scaffold is removed, followed by loss of the presynaptic terminal. GABARs are endocytosed during GCI, but how this process accompanies synapse disassembly remains unclear. Here, we define the precise trafficking itinerary of GABARs during the initial stages of GCI, placing them in the context of rapid synapse elimination. Ischemia-induced GABAR internalization quickly follows their initial dispersal from the synapse, and is controlled by PP1α signaling. During reperfusion injury, GABARs are then trafficked to lysosomes for degradation, leading to permanent removal of synaptic GABARs and contributing to the profound reduction in synaptic inhibition observed hours following ischemia onset.