Excitotoxicity

To understand why some neurons die while nearby neurons are spared in a nonrandom manner, much research has focused on the pattern of excitatory and inhibitory receptors on particular neuronal populations. Anoxic depolarization results in the release of excitatory and inhibitory neu-rotransmitters. Impaired reuptake by energy-dependent mechanisms results in large increases in intrasynaptic and extrasynaptic concentrations of neurotransmitters. In the case of the primary excitatory neurotransmitter glutamate, reuptake largely depends on transporters in astrocytes and neurons that are driven by the high extracellular-to-intracellular Na+ gradient that is normally maintained by Na,K-ATPase. This gradient is lost during anoxic depolarization but can gradually recover during reperfusion (3). After some delay in the restoration of ATP production during reperfusion, extrasynaptic glutamate concentration measured by microdialysis is reduced (36). However, intrasynaptic glutamate concentration may not necessarily be restored uniformly because of persistent swelling in astrocyte and dendritic processes associated with incomplete and heterogeneous restoration of ionic gradients and energy metabolism. Thus, glutamate may continue to act on its excitatory ionotropic receptors, not only during ischemia but also during the reperfusion period, when other cellular processes are recovering and continued Ca2+ signaling could have adverse effects. Glutamate acting on the AMPA receptor would continue to enhance Na+ entry, keep the cells in a partially depolarized state, and thereby promote Ca2 + entry through voltage-dependent Ca2 + channels. Additionally, AMPA

receptors that lack the GluR2 subunit also permit direct Ca2+ entry. Decreased expression of GluR2 subunits has been described in hippocampus over the first few days of reperfusion (37). Glutamate acting on NMDA receptors also permits Ca2+ entry. Moreover, phosphorylation of NMDA receptors occurs during the reperfusion period (38,39) and thereby alters the function of the receptor and channel. Enhanced Ca2+ entry in neurons with excitatory receptors is thought to lead to selective vulnerability of these neurons. In that many of these neurons release gamma-aminobutyric acid (GABA) as their neurotransmitter, selective loss of neurons with inhibitory output is thought to create an imbalance of excitation and inhibition, which contributes to the secondary injury of selectively vulnerable neurons during reperfusion.

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