Transient receptor potential vanilloid 4 is involved in the upregulation of connexin expression following pilocarpine-induced status epilepticus in mice.

Epilepsy is characterized by spontaneous seizures. Changes in the expression of the connexins (Cxs) have been reported to be involved in epileptogenesis. It has previously been shown that the transient receptor potential vanilloid 4 (TRPV4) plays an important role in the modulation of neuronal excitability, and that application of a TRPV4 antagonist blocks hyperthermia-induced seizures. Accordingly, in the present study, we sought to explore whether TRPV4 is involved in the regulation of Cx expression following pilocarpine-induced status epilepticus (PISE) in mice. We observed that TRPV4 protein levels in hippocampi increased 3 h to 30 d following PISE, peaking 1-3 d after induction, and that pre-application of the TRPV4 antagonist HC-067047 increased the latency to develop SE induced by pilocarpine and reduced the success rate of PISE preparation. We demonstrated that Cx43 protein levels followed a time profile similar to that of TRPV4, and further showed that the increase in Cx43 protein levels on 3 d post-PISE was markedly attenuated by HC-067047. In contrast, the corresponding increase in Cx32 protein levels lagged substantially behind, and these levels were unaffected by HC-067047. Similarly, the TRPV4 agonist GSK1016790A increased the mRNA and protein levels of Cx43, but not those of Cx32. We thus conclude that the upregulation of Cx43 expression by TRPV4 may be involved in the pathophysiology of epilepsy.

Author Correction: TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice.

The article contains an error in Fig. 3. This has now been corrected in both the PDF and HTML versions of the article, and the correct version of Fig. 3 is shown in the accompanying Author Correction.

TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice.

Activation of transient receptor potential vanilloid 4 (TRPV4) induces neuronal injury. TRPV4 activation enhances inflammatory response and promotes the proinflammatory cytokine release in various types of tissue and cells. Hyperneuroinflammation contributes to neuronal damage in epilepsy. Herein, we examined the contribution of neuroinflammation to TRPV4-induced neurotoxicity and its involvement in the inflammation and neuronal damage in pilocarpine model of temporal lobe epilepsy in mice. Icv. injection of TRPV4 agonist GSK1016790A (GSK1016790A-injected mice) increased ionized calcium binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) protein levels and Iba-1-positive (Iba-1+) and GFAP-positive (GFAP+) cells in hippocampi, which indicated TRPV4-induced microglial cell and astrocyte activation. The protein levels of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome components NLRP3, apoptosis-related spotted protein (ASC) and cysteinyl aspartate-specific protease-1 (caspase-1) were increased in GSK1016790A-injected mice, which indicated NLRP3 inflammasome activation. GSK1016790A also increased proinflammatory cytokine IL-1ß, TNF-α and IL-6 protein levels, which were blocked by caspase-1 inhibitor Ac-YVAD-cmk. GSK1016790A-induced neuronal death was attenuated by Ac-YVAD-cmk. Icv. injection of TRPV4-specific antagonist HC-067047 markedly increased the number of surviving cells 3 d post status epilepticus in pilocarpine model of temporal lobe epilepsy in mice (pilocarpine-induced status epilepticus, PISE). HC-067047 also markedly blocked the increase in Iba-1 and GFAP protein levels, as well as Iba-1+ and GFAP+ cells 3 d post-PISE. Finally, the increased protein levels of NLRP3, ASC and caspase-1 as well as IL-1ß, TNF-α and IL-6 were markedly blocked by HC-067047. We conclude that TRPV4-induced neuronal death is mediated at least partially by enhancing the neuroinflammatory response, and this action is involved in neuronal injury following status epilepticus.

Transient Receptor Potential Vanilloid 4 Activation-Induced Increase in Glycine-Activated Current in Mouse Hippocampal Pyramidal Neurons.

BACKGROUND/AIMS: Glycine plays an important role in regulating hippocampal inhibitory/ excitatory neurotransmission through activating glycine receptors (GlyRs) and acting as a co-agonist of N-methyl-d-aspartate-type glutamate receptors. Activation of transient receptor potential vanilloid 4 (TRPV4) is reported to inhibit hippocampal A-type γ-aminobutyric acid receptor, a ligand-gated chloride ion channel. GlyRs are also ligand-gated chloride ion channels and this paper aimed to explore whether activation of TRPV4 could modulate GlyRs. METHODS: Whole-cell patch clamp recording was employed to record glycine-activated current (IGly) and Western blot was conducted to assess GlyRs subunits protein expression. RESULTS: Application of TRPV4 agonist (GSK1016790A or 5,6-EET) increased IGly in mouse hippocampal CA1 pyramidal neurons. This action was blocked by specific antagonists of TRPV4 (RN-1734 or HC-067047) and GlyR (strychnine), indicating that activation of TRPV4 increases strychnine-sensitive GlyR function in mouse hippocampal pyramidal neurons. GSK1016790A-induced increase in IGly was significantly attenuated by protein kinase C (PKC) (BIM II or D-sphingosine) or calcium/calmodulin-dependent protein kinase II (CaMKII) (KN-62 or KN-93) antagonists but was unaffected by protein kinase A or protein tyrosine kinase antagonists. Finally, hippocampal protein levels of GlyR α1 α2, α3 and ß subunits were not changed by treatment with GSK1016790A for 30 min or 1 h, but GlyR α2, α3 and ß subunits protein levels increased in mice that were intracerebroventricularly (icv.) injected with GSK1016790A for 5 d. CONCLUSION: Activation of TRPV4 increases GlyR function and expression, and PKC and CaMKII signaling pathways are involved in TRPV4 activation-induced increase in IGly. This study indicates that GlyRs may be effective targets for TRPV4-induced modulation of hippocampal inhibitory neurotransmission.

Surface vector plasmonic lattice solitons in semi-infinite graphene-pair arrays.

We investigate the surface vector plasmonic lattice solitons (PLSs) in semi-infinite graphene-pair arrays (GPAs). The surface vector PLSs are composed of two components which are associated with different band gaps. Both components undergo mutual self-trapping at the boundary of the semi-infinite structure when the self-focusing nonlinearity of graphene and the light diffraction reach a balance. Thanks to the strong confinement of SPPs, the surface vector PLSs can be squeezed into a deep-subwavelength width of ~0.003λ. By comparing with bulk solitons, the surface PLSs are more readily to excite by external waves and more sensitive to the surrounding environment. The study may develop promising applications in all-optical switching devices and optical sensors on deep-subwavelength scale.

Activation of Transient Receptor Potential Vanilloid 4 Impairs the Dendritic Arborization of Newborn Neurons in the Hippocampal Dentate Gyrus through the AMPK and Akt Signaling Pathways.

Neurite growth is an important process for the adult hippocampal neurogenesis which is regulated by a specific range of the intracellular free Ca2+ concentration ([Ca2+]i). Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable channel and activation of it causes an increase in [Ca2+]i. We recently reported that TRPV4 activation promotes the proliferation of stem cells in the adult hippocampal dentate gyrus (DG). The present study aimed to examine the effect of TRPV4 activation on the dendrite morphology of newborn neurons in the adult hippocampal DG. Here, we report that intracerebroventricular injection of the TRPV4 agonist GSK1016790A for 5 days (GSK1016790A-injected mice) reduced the number of doublecortin immunopositive (DCX+) cells and DCX+ fibers in the hippocampal DG, showing the impaired dendritic arborization of newborn neurons. The phosphorylated AMP-activated protein kinase (p-AMPK) protein level increased from 30 min to 2 h, and then decreased from 1 to 5 days after GSK1016790A injection. The phosphorylated protein kinase B (p-Akt) protein level decreased from 30 min to 5 days after GSK1016790A injection; this decrease was markedly attenuated by the AMPK antagonist compound C (CC), but not by the AMPK agonist AICAR. Moreover, the phosphorylated mammalian target of rapamycin (mTOR) and p70 ribosomal S6 kinase (p70S6k) protein levels were decreased by GSK1016790A; these changes were sensitive to 740 Y-P and CC. The phosphorylation of glycogen synthase kinase 3ß (GSK3ß) at Y216 was increased by GSK1016790A, and this change was accompanied by increased phosphorylation of microtubule-associated protein 2 (MAP2) and collapsin response mediator protein-2 (CRMP-2). These changes were markedly blocked by 740 Y-P and CC. Finally, GSK1016790A-induced decrease of DCX+ cells and DCX+ fibers was markedly attenuated by 740 Y-P and CC, but was unaffected by AICAR. We conclude that TRPV4 activation impairs the dendritic arborization of newborn neurons through increasing AMPK and inhibiting Akt to inhibit the mTOR-p70S6k pathway, activate GSK3ß and thereby result in the inhibition of MAP2 and CRMP-2 function.

Asymmetric plasmonic supermodes in nonlinear graphene multilayers.

We investigate the nonlinear supermodes of surface plasmon polaritons in graphene multilayers with arbitrary number of graphene layers. Apart from the symmetric and anti-symmetric supermodes which exist in linear multilayer graphene waveguides, more asymmetric supermodes emerge in the nonlinear counterparts as the field symmetry is broken. The number of asymmetric supermodes relies largely on the layer number of graphene. There is a certain threshold of field intensity for the emergence of each individual asymmetric supermode. The threshold increases as the incident wavelength or chemical potential of graphene increases. The study may find applications in building all-optical mode converters and switches.

Vector plasmonic lattice solitons in nonlinear graphene-pair arrays.

We investigate the vector plasmonic lattice solitons (PLSs) in nonlinear graphene-pair arrays (GPAs) consisting of periodically arranged double graphene sheets, which are spatially separated. There are two dispersion bands for the Bloch modes in the array due to the coupling of surface plasmon polaritons (SPPs) between the graphene pairs. The vector PLSs composed of two components originate from the nonlinear interaction of Bloch modes in different bands. Both components undergo mutual self-trapping through the balance between diffraction and self-focusing nonlinearity of graphene. Thanks to the strong confinement of SPPs, the vector PLSs can be squeezed into a lateral width of ∼λ/100. The study provides a promising approach to all-optical control on a deep-subwavelength scale.

Plasmonic lattice solitons in nonlinear graphene sheet arrays.

We investigate the plasmonic lattice solitons (PLSs) in nonlinear graphene sheet arrays (GSAs) composed of spatially separated graphene sheets embedded in dielectric. Both the nonlinearities of graphene and dielectric are considered. The self-focusing PLSs at the Brillouin zone edges can be yielded by balancing the normal diffraction of surface plasmon polaritons (SPPs) via either the nonlinear effect of graphene or self-focusing dielectric. The self-defocusing PLSs corresponding to anomalous diffraction of SPPs at the Brillouin zone center could be yielded by the nonlinearity of self-defocusing dielectric alone. The width and propagation distance of the PLSs are dependent on the period of the GSAs and the chemical potential of graphene. Thanks to the strong confinement of SPPs, the PLSs in GSAs can be squeezed into an effective width as small as λ/250. The study may find applications in optical circuits and switches on deep-subwavelength scale.