PMC

SR^−/− mice display NMDA receptor supersensitivity. A, NMDA receptor NR1, but not NR2, subunit expression is increased in SR^−/− brains. B, NMDA-elicited lesion volume is increased by nearly 50% in the striatum of SR^−/− animals compared with wild-type (WT) littermate controls (n = 15 animals each). C, Representative images of a wild-type and SR^−/− brain post-NMDA injection into the corpus striatum. SR^−/− mice display increased lesion area (contours delineated by dotted lines) compared with wild-type littermates. *p < 0.05, **p < 0.01, ***p < 0.001.

Neurotoxicity is markedly reduced in SR-deleted cerebral cortical cultures. A, NO generation, measured using the NO-specific dye DAF-FM DA, is markedly diminished in SR^−/− cultures. B, nNOS protein expression is similar in wild-type (WT) and SR^−/− neurons. C, SR^−/− neurons display diminished cell death under OGD as indicated by a lower ratio of propidium iodide (label for dead cells) to Hoechst 33258 stain (nuclear label for all cells). D, Quantitation of cell death from OGD shows a 50% reduction in SR^−/− neurons. *p < 0.05, **p < 0.01, ***p < 0.001.

SR deletion protects against focal cerebral ischemia. A, Infarct volume following MCAO is reduced by 61% in the cerebral hemispheres, 60% in the cerebral cortex, and 43% in the caudate–putamen (CP) region of the SR^−/− mice compared with wild-type (WT) littermate controls (n = 9 animals each). B, Representative images of a wild-type and SR^−/− brain 24 h post-MCAO. SR^−/− mice display marked reduction in infarct area (contours delineated by dotted lines) compared with wild-type littermates. *p < 0.05, **p < 0.01, ***p < 0.001.

Synthesis of nitric oxide and protein S-nitrosylation are decreased in SR^−/− brains. A, NO generation in wild-type (WT), SR^−/−, and nNOS^−/− brain slices. NO generation is reduced by ∼70% in SR^−/− slices compared with wild-type controls. As nNOS is the primary NOS isozyme responsible for NO formation in the brain, nNOS^−/− mice display almost complete absence of NO generation. B, S-nitrosylation (SNO) of GAPDH is markedly reduced in SR^−/− brain and absent in nNOS^−/− preparations. nNOS is expressed equally in wild-type and SR^−/− brain tissues. C, Relative densitometric quantitation of protein S-nitrosylation in wild-type versus SR^−/− brains reveals a pronounced reduction (70–90%) in S-nitrosylation of GAPDH, β-tubulin, and the NR1 subunit of the NMDA receptor in SR-deleted animals. *p < 0.05, **p < 0.01, ***p < 0.001.