TRPM2-CaMKII signaling drives excessive GABAergic synaptic inhibition following ischemia

Abstract

Following an ischemic insult to the brain, there is an acute loss of GABAergic inhibitory synapses and an increase in excitatory/ inhibitory (E/I) imbalance that drives neuronal hyperexcitability. It is unknown whether this E/I imbalance persists at delayed timepoints and contributes to chronic impairments in memory and long-term potentiation (LTP) in the hippocampus following ischemic brain injury. Here, we reveal a shift to reduced E/I ratio in hippocampal CA1 neurons via a persistent increase in postsynaptic GABAAreceptor mediated inhibitory responses and clustering days after a global ischemic insult. This enhancement of postsynaptic inhibitory function and clustering required activation of the Ca2+-permeable TRPM2 ion channel and the Ca2+-dependent kinase, CaMKII. Thus, we propose a mechanism in which acute downregulation of GABAAreceptors is followed by a strengthening of inhibitory synapses at delayed periods after ischemia. Targeting this mechanism has therapeutic potential to recover hippocampal plasticity and cognitive function post-ischemia.GRAPHICAL ABSTRACT