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bioRxiv · 10.1101/2023.09.07.556550

TRPM2-CaMKII signaling drives excessive GABAergic synaptic inhibition following ischemia

Burch, A. M.·Garcia, J. D.·O'Leary, H.·Haas, A.·Orfila, J. E.·Tiemeier, E.·Chalmers, N.·Smith, K. R.·Quillinan, N.·Herson, P. S.
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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 GABAA receptor 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 GABAA receptors 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/556550v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@16ef5f2org.highwire.dtl.DTLVardef@1d51f19org.highwire.dtl.DTLVardef@ecc726org.highwire.dtl.DTLVardef@106cdd0_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Burch, A. M., Garcia, J. D., O'Leary, H., Haas, A., Orfila, J. E., Tiemeier, E., Chalmers, N., Smith, K. R., Quillinan, N., Herson, P. S.. 2023-09-09. TRPM2-CaMKII signaling drives excessive GABAergic synaptic inhibition following ischemia. https://doi.org/10.1101/2023.09.07.556550

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