Distinct mechanisms drive sequential internalization and degradation of GABA_ARs during global ischemia and...

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: GABA_ARs are rapidly trafficked away from the synapse, the gephyrin scaffold is removed, followed by loss of the presynaptic terminal. GABA_ARs are endocytosed during GCI, but how this process accompanies synapse disassembly remains unclear. Here, we define the precise trafficking itinerary of GABA_ARs during the initial stages of GCI, placing them in the context of rapid synapse elimination. Ischemia-induced GABA_AR internalization quickly follows their initial dispersal from the synapse, and is controlled by PP1α signaling. During reperfusion injury, GABA_ARs are then trafficked to lysosomes for degradation, leading to permanent removal of synaptic GABA_ARs and contributing to the profound reduction in synaptic inhibition observed hours following ischemia onset.