Excessive Na+/H+ exchange in disruption of dendritic Na+and Ca2+ homeostasis and mitochondrial dysfunction following in vitro ischemia

Abstract

Neuronal dendrites are vulnerable to injury under diverse pathological conditions. However, the underlying mechanisms for dendritic Na+ overload and the selective dendritic injury remain poorly understood. Our current study demonstrates that activation of NHE-1 (Na+/H + exchanger isoform 1) in dendrites presents a major pathway for Na+ overload. Neuronal dendrites exhibited higher pHi regulation rates than soma as a result of a larger surface area/volume ratio. Following a 2-h oxygen glucose deprivation and a 1-h reoxygenation, NHE-1 activity was increased by ∼70-200% in dendrites. This elevation depended on activation of p90 ribosomal S6 kinase. Moreover, stimulation of NHE-1 caused dendritic Na+i accumulation, swelling, and a concurrent loss of Ca2+i homeostasis. The Ca2+i overload in dendrites preceded the changes in soma. Inhibition of NHE-1 or the reverse mode of Na+/Ca2+ exchange prevented these changes. Mitochondrial membrane potential in dendrites depolarized 40 min earlier than soma following oxygen glucose deprivation/ reoxygenation. Blocking NHE-1 activity not only attenuated loss of dendritic mitochondrial membrane potential and mitochondrial Ca2+ homeostasis but also preserved dendritic membrane integrity. Taken together, our study demonstrates that NHE-1-mediated Na+ entry and subsequent Na+/Ca2+ exchange activation contribute to the selective dendritic vulnerability to in vitro ischemia. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.