Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1·GTP pathway

Abstract

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 Rac1⅐GTP. 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 Rac1⅐GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1⅐GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radicalsensitive ER-mitochondrion-Rac1⅐GTP pathway in the regulation of dendritic spine formation in the hippocampus. mitochondria ͉ ROS ͉ N-acetyl cyteine ͉ learning and memory ͉ caspase-3 D endritic spines in the CNS are important for many functions. Dendritic atrophy in the neocortical region is related to aging-induced amnesia, and its reversal improves memory retention (1). Similarly, the loss of dendritic spine-related synapses is currently a strong pathologic correlate of cognitive decline, and synaptic dysfunction is evident long before synapses and neurons are lost (2). On the other hand, exposure to drugs of abuse including cocaine, nicotine, or morphine produces persistent changes, usually in the form of increased dendritic spines and arborizations, in cells in brain regions involved in incentive motivation and reward (3). These persistent changes are thought to represent the neuronal reorganization that contributes to some of the persistent sequelae associated with drug use, including the establishment of motivational conditioning and learning (3).The morphology of dendritic spines and axons is determined by the dynamic cytoskeleton protein actin. Rho family small GTPases including Rho, Cdc42, and Rac1 regulate the dynamics of actin and are critical for neuronal polarization and morphogenesis (4-6). Rho proteins are regulated by guanine nucleotide exchange factors (GEFs). In early stages of neural morphogenesis, the activation of Cdc42 promotes the formation of filopodia, the long thin protrusions serving as primary precursors of axons and dendritic spines (7). However, Ra...

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

“…Sig-1Rs have been implicated in many physiological functions (3,10,13,(42)(43)(44)(45)(46)(47). Our results from the present study add an additional function of Sig-1R, in that it regulates gene expression at the NE.…”

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

“…We previously reported that rat hippocampal neurons transfected with Sig-1R siRNA (siSig-1R) displayed reduced dendritic spine formation compared with control siRNA (siCon) cells (28). This led us to further examine the role of Sig-1Rs in neuronal morphology.…”

“…The underlying molecular mechanisms of Sig-1R action remain to be totally clarified. Although we have previously demonstrated several versatile actions of Sig-1Rs as they may affect cellular survival (26)(27)(28), other mechanisms of action may exist. Here, we have identified a new action of Sig-1Rs in that Sig-1Rs regulate tau phosphorylation and axon elongation by interacting with myristic acid.…”

“…The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) chaperone that resides at the ER/mitochondrion interface referred to as the mitochondrion-associated ER membrane (26)(27)(28) that has been implicated in neurodegenerative disorders (29)(30)(31). The exact molecular mechanism underlying the neuroprotective property of Sig-1Rs remains to be totally clarified.…”

“…The exact molecular mechanism underlying the neuroprotective property of Sig-1Rs remains to be totally clarified. Although we previously reported that Sig-1Rs promote dendritic arborization (28), whether Sig-1Rs are involved in the regulation of axon elongation remains unknown. A recent report demonstrated the efficacy of a Sig-1R ligand in attenuating the β-amyloid-induced neurotoxicity via the ligand's action in blocking the glycogen…”