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

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 pH(i) 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 Ca(2+)(i) homeostasis. The Ca(2+)(i) overload in dendrites preceded the changes in soma. Inhibition of NHE-1 or the reverse mode of Na(+)/Ca(2+) 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 Ca(2+) homeostasis but also preserved dendritic membrane integrity. Taken together, our study demonstrates that NHE-1-mediated Na(+) entry and subsequent Na(+)/Ca(2+) exchange activation contribute to the selective dendritic vulnerability to in vitro ischemia.