Synaptic Zn Contributes to Deleterious Consequences of Spreading Depolarizations

Overview

Journal bioRxiv

Date 2023 Nov 14

PMID 37961648

Authors

Michael C Bennett

Russell A Morton

Andrew P Carlson

C William Shuttleworth

Affiliations

Soon will be listed here.

Abstract

Spreading depolarizations (SDs) are profound waves of neuroglial depolarization that can propagate repetitively through injured brain. Recent clinical work has established SD as an important contributor to expansion of acute brain injuries and have begun to extend SD studies into other neurological disorders. A critical challenge is to determine how to selectively prevent deleterious consequences of SD. In the present study, we determined whether a wave of profound Zn release is a key contributor to deleterious consequences of SD, and whether this can be targeted pharmacologically. Focal KCl microinjection was used to initiate SD in the CA1 region of the hippocampus in murine brain slices. An extracellular Zn chelator with rapid kinetics (ZX-1) increased SD propagation rates and improved recovery of extracellular DC potential shifts. Under conditions of metabolic compromise, tissues showed sustained impairment of functional and structural recovery following a single SD. ZX-1 effectively improved recovery of synaptic potentials and intrinsic optical signals in these vulnerable conditions. Fluorescence imaging and genetic deletion of a presynaptic Zn transporter confirmed synaptic release as the primary contributor to extracellular accumulation and deleterious consequences of Zn during SD. These results demonstrate a role for synaptic Zn release in deleterious consequences of SD and show that targeted extracellular chelation could be useful for disorders where repetitive SD enlarges infarcts in injured tissues.

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