Molecular and cellular neurosciences
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Mol. Cell. Neurosci. · Sep 2013
Necl-2/CADM1 interacts with ErbB4 and regulates its activity in GABAergic neurons.
The neuronal network is tightly regulated by a large variety of locally connected GABAergic neurons. Neuregulin1 (Nrg1) and its receptor ErbB4 are master regulators in the morphological and functional development of excitatory synapses in GABAergic neurons. We previously showed that the immunoglobulin-like cell adhesion molecule, nectin-like molecule-2 (Necl-2)/CADM1, interacts with the ErbB3 and ErbB4 receptors, and that the interaction of Necl-2 with ErbB3 inhibits the Nrg1-induced ErbB3/ErbB2 signaling in epithelial cells. ⋯ Necl-2 knockdown enhanced the Nrg1-induced phosphorylation of ErbB4. Moreover, overexpression of PTPN13, which is a tyrosine phosphatase bound to the cytoplasmic tail of Necl-2, suppressed the Nrg1-induced development of excitatory synapses in GABAergic neurons through the inhibition of ErbB4 activity. These results indicate that Necl-2 interacts with ErbB4 and regulates the development of excitatory synapses via the regulation of ErbB4 activity in GABAergic neurons.
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Mol. Cell. Neurosci. · Sep 2013
Fluoxetine and citalopram decrease microglial release of glutamate and D-serine to promote cortical neuronal viability following ischemic insult.
Depression is one of the most common disorders appearing following a stroke, and is also a major factor limiting recovery and rehabilitation in stroke patients. Antidepressants are the most common prescribed treatment for depression and have shown to have anti-inflammatory properties within the central nervous system (CNS). The major source of pro-inflammatory factors within the CNS is from activated microglia, the innate immune cells of the CNS. ⋯ Fluoxetine and citalopram, the SSRIs, decreased the release of the amino acids glutamate and d-serine from LPS-activated microglia. oxygen-glucose deprived (OGD) cortical neurons cocultured with LPS-activated microglia pre-treated with fluoxetine and citalopram showed greater survival compared to injured neurons co-cultured with untreated activated microglia. Microglial release of glutamate and d-serine was shown to be the most important factor mediating neuronal survival following antagonism studies. To our knowledge, our results demonstrate for the first time that fluoxetine and citalopram decrease the release of glutamate and d-serine from LPS-activated microglia and this causes an increase in the survival of OGD-injured cortical neurons after co-culture.
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Mol. Cell. Neurosci. · Sep 2013
Differential role of Dok1 and Dok2 in TLR2-induced inflammatory signaling in glia.
Accumulating evidence continues to underpin the role of the innate immune system in pathologies associated with neuroinflammation. Innate immunity is regulated by pattern recognition receptors that detect pathogens, and in the case of Gram-positive bacteria, binding of bacterial lipopeptides to toll-like receptor (TLR)2 is emerging as an important mechanism controlling glial cell activation. In the present study, we employed the use of the synthetic bacterial lipoprotein and a selective TLR2 agonist, Pam3CSK4, to induce inflammatory signaling in microglia and astrocytes. ⋯ Importantly, TLR2-induced NF-κB activation, and IL-6 production was exacerbated in astrocytes transfected with Dok1 and Dok2 siRNA, indicating that both Dok proteins negatively regulate TLR2-induced inflammatory signaling in astrocytes. In contrast, Dok1 knockdown attenuated TLR2-induced NF-κB activation and IL-6 production in microglia, while Dok2 siRNA failed to affect TLR2-induced NF-κB activity and subsequent cytokine expression in this cell type. Overall, this indicates that Dok1 and Dok2 are novel adaptors for TLR2 in glial cells and importantly indicates that Dok1 and Dok2 differentially regulate TLR2-induced pro-inflammatory signaling in astrocytes and microglia.
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Mol. Cell. Neurosci. · May 2013
Impaired basal and running-induced hippocampal neurogenesis coincides with reduced Akt signaling in adult R6/1 HD mice.
Huntington's disease (HD) is a fatal neurodegenerative disorder affecting a range of cellular and molecular functions in the brain. Deficits in adult hippocampal neurogenesis (AHN) have been documented in the R6/1 mouse model of HD. Here we examined basal and running-induced neuronal precursor proliferation in adult female and male R6/1 HD mice. ⋯ Running induced Akt phosphorylation in the hippocampus of female wildtype mice, which was not reflected in R6/1 HD mice. Total Akt levels were decreased in the hippocampus of both control and running R6/1 HD mice. Our results show adult-generated hippocampal neurons in female R6/1 HD mice express c-Fos and that running and Akt signaling deficits may mediate reduced basal and running-induced AHN levels.
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Mol. Cell. Neurosci. · Jan 2013
Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia.
In addition to the proinflammatory cytokines tumor necrosis factor-α, interleukin-6 and interleukin-1ß, the cytokine interleukin-17 (IL-17) is considered an important mediator of autoimmune diseases such as rheumatoid arthritis. Because tumor necrosis factor-α and interleukin-1ß have the potential to influence the expression of transduction molecules such as transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons and thus to contribute to pain we explored in the present study whether IL-17A activates DRG neurons and influences the expression of TRPV1. The IL-17A receptor was visualized in most neurons in dorsal root ganglion (DRG) sections as well as in cultured DRG neurons. ⋯ However, we found a pronounced upregulation of transient receptor potential vanilloid 4 (TRPV4) which is considered a candidate transduction molecule for mechanical hyperalgesia. Upon the injection of zymosan into the paw, IL-17A-deficient mice showed less mechanical hyperalgesia than wild type mice but thermal hyperalgesia was not attenuated in IL-17A-deficient mice. These data show, therefore, a particular role of IL-17 in mechanical hyperalgesia, and they suggest that this effect is linked to an activation and upregulation of TRPV4.