Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1xGTP pathway.
Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER)-resident proteins known to be involved in learning and memory. Dendritic spines in hippocampal neurons play important roles in neuroplasticity and learning and memory. This study tested the hypothesis that Sig-1Rs might regulate denritic spine formation in hippocampal neurons and examined potential mechanisms therein. In rat hippocampal primary neurons, the knockdown of Sig-1Rs by siRNAs causes a deficit in the formation of dendritic spines that is unrelated to ER Ca(2+) signaling or apoptosis, but correlates with the mitochondrial permeability transition and cytochrome c release, followed by caspase-3 activation, Tiam1 cleavage, and a reduction in Rac1.GTP. Sig-1R-knockdown neurons contain higher levels of free radicals when compared to control neurons. The activation of superoxide dismutase or the application of the hydroxyl-free radical scavenger N-acetyl cysteine (NAC) to the Sig-1R-knockdown neurons rescues dendritic spines and mitochondria from the deficits caused by Sig-1R siRNA. Further, the caspase-3-resistant TIAM1 construct C1199DN, a stable guanine exchange factor able to constitutively activate Rac1 in the form of Rac1.GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1.GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radical-sensitive ER-mitochondrion-Rac1.GTP pathway in the regulation of dendritic spine formation in the hippocampus.
Tsai
Shang-Yi
SY
Cellular Pathobiology Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, 333 Cassell Drive, Baltimore, MD 21224, USA.
Hayashi
Teruo
T
Harvey
Brandon K
BK
Wang
Yun
Y
Wu
Wells W
WW
Shen
Rong-Fong
RF
Zhang
Yongqing
Y
Becker
Kevin G
KG
Hoffer
Barry J
BJ
Su
Tsung-Ping
TP
D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007858:Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D016166:Free Radical Scavengers; D005609:Free Radicals; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D017480:Receptors, sigma; D011994:Recombinant Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513259:Tiam1 protein, rat; C101491:sigma1-binding protein, rat; D006160:Guanosine Triphosphate; C505410:Casp3 protein, rat; D053148:Caspase 3; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein