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The Journal of Neuroscience, July 13, 2005, 25(28):6561-6575; doi:10.1523/JNEUROSCI.1450-05.2005

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Cellular/Molecular
Mitochondrial Nitric Oxide Mediates Decreased Vulnerability of Hippocampal Neurons from Immature Animals to NMDA

Jeremy D. Marks,^1,2,3 Chan Boriboun,¹ and Janice Wang¹

¹Department of Pediatrics and the Committees on ²Cell Physiology and ³Molecular Medicine, University of Chicago, Chicago, Illinois 60637

Mitochondrial membrane potential (_m)-dependent Ca²⁺ uptake plays a central role in neurodegeneration after NMDA receptor activation. NMDA-induced _m dissipation increases during postnatal development, coincident with increasing vulnerability to NMDA. NMDA receptor activation also produces nitric oxide (NO), which can inhibit mitochondrial respiration, dissipating _m. Because _m dissipation reduces mitochondrial Ca²⁺ uptake, we hypothesized that NO mediates the NMDA-induced _m dissipation in immature neurons, underlying their decreased vulnerability to excitotoxicity. Using hippocampal neurons cultured from 5- and 19-d-old rats, we measured NMDA-induced changes in [Ca²⁺]_cytosol, _m, NO, and [Ca²⁺]_mito. In postnatal day 5 (P5) neurons, NMDA mildly dissipated _m in a NO synthase (NOS)-dependent manner and increased NO. The NMDA-induced NO increase was abolished with carbonyl cyanide 4-(trifluoromethoxy)phenyl-hydrazone and regulated by [Ca²⁺]_mito. Mitochondrial Ca²⁺ uptake inhibition prevented the NO increase, whereas inhibition of mitochondrial Ca²⁺ extrusion increased it. Consistent with this mitochondrial regulation, NOS and cytochrome oxidase immunoreactivity demonstrated mitochondrial localization of NOS. Furthermore, NOS blockade increased mitochondrial Ca²⁺ uptake during NMDA. Finally, at physiologic O₂ tensions (3% O₂), NMDA had little effect on survival of P5 neurons, but NOS blockade during NMDA markedly worsened survival, demonstrating marked neuroprotection by mitochondrial NO. In P19 neurons, NMDA dissipated _m in an NO-insensitive manner. NMDA-induced NO production was not regulated by _m, and NOS immunoreactivity was cytosolic, without mitochondrial localization. NOS blockade also protected P19 neurons from NMDA. These data demonstrate that mitochondrial NOS mediates much of the decreased vulnerability to NMDA in immature hippocampal neurons and that cytosolic NOS contributes to NMDA toxicity in mature neurons.

Key words: NMDA; mitochondria; nitric oxide; calcium; development; mtNOS

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Received Oct 2, 2003; revised May 27, 2005; accepted May 28, 2005.

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