Lack of JWA Enhances Neurogenesis and Long-Term Potentiation in Hippocampal Dentate Gyrus Leading to Spatial Cognitive Potentiation.

JWA (Arl6ip5), a homologous gene of glutamate-transporter-associated protein 3-18 (GTRAP3-18) and addicsin, is highly expressed in hippocampus. We generated systemic and neuronal JWA knockout (JWA-KO and JWA-nKO) mice to investigate the influence of JWA deficiency on spatial cognitive performance, process of neurogenesis, and induction of long-term potentiation (LTP) in hippocampal dentate gyrus (DG). In comparison with wild-type (WT) mice and JWA (loxP/loxP) (control of JWA-nKO) mice, 8-week-old JWA-KO mice and JWA-nKO mice showed spatial cognitive potentiation as assessed by Morris water maze test. In hippocampal DG of JWA-nKO mice, either survival and migration or neurite growth of newborn neurons were significantly enhanced without the changes in proliferation and differentiation of stem cells. In addition, the increase of LTP amplitude and the decline of LTP threshold were observed in DG, but not in CA1 region, of JWA-nKO mice compared to control mice. The levels of hippocampal FAK, Akt, and mTOR phosphorylation in JWA-nKO mice were higher than those in control mice. The PI3K or FAK inhibitor could abolish the enhanced neurogenesis and LTP induction in JWA-nKO mice, which was accompanied by disappearance of the spatial cognitive potentiation. The treatment of JWA-nKO mice with 3'-azido-3'-deoxythymidine (AZT), a telomerase inhibitor, suppressed not only the enhanced neurogenesis but also the enhanced LTP induction in DG, but it did not affect the LTP induction in CA1 region. The results suggest that the JWA deficiency through cascading FAK-PI3K-Akt-mTOR pathway increases the newborn neurons and enhances the LTP induction in hippocampal DG, which leads to the spatial cognitive potentiation.

Sex-related neurogenesis decrease in hippocampal dentate gyrus with depressive-like behaviors in sigma-1 receptor knockout mice.

Male sigma-1 receptor knockout (σ1R(-/-)) mice showed depressive-like phenotype with deficit in the survival of newly generated neuronal cells in the hippocampal dentate gyrus (DG), but female σ1R(-/-) mice did not. The level of serum estradiol (E2) at proestrus or diestrus did not differ between female σ1R(-/-) mice and wild-type (WT) mice. Ovariectomized (OVX) female σ1R(-/-) mice, but not WT mice, presented the same depressive-like behaviors and neurogenesis decrease as male σ1R(-/-) mice. Treatment of male σ1R(-/-) mice with E2 could alleviate the depressive-like behaviors and rescue the neurogenesis decrease. In addition, E2 could correct the decline in the density of NMDA-activated current (INMDA) in granular cells of DG and the phosphorylation of NMDA receptor (NMDAr) subtype 2B (NR2B) in male σ1R(-/-) mice, which was associated with the elevation of Src phosphorylation. The neuroprotection and antidepressant effects of E2 in male σ1R(-/-) mice were blocked by the inhibitor of Src or NR2B. The NMDAr agonist showed also the neuroprotection and antidepressant effects in male σ1R(-/-) mice, which were insensitive to the Src inhibitor. On the other hand, either the deprivation of E2 or the inhibition of Src in female σ1R(-/-) mice rather than WT mice led to a distinct decline in INMDA and NR2B phosphorylation. Similarly, the Src inhibitor could cause neurogenesis decrease and depressive-like behaviors in female σ1R(-/-) mice, but not in WT mice. These results indicate that the σ1R deficiency impairs neurogenesis leading to a depressive-like phenotype, which is alleviated by the neuroprotection of E2.

Simvastatin exerts antiamnesic effect in Aß25-35 -injected mice.

AIM AND METHODS: Simvastatin (SV) is reported to improve cognition and slow the progression of Alzheimer's disease (AD). This study explored the mechanisms underlying the antiamnesic effect of SV in AD using behavior tests, histological examination, western blot analysis, and electrophysiological recording technique in AD model mice created by intracerebroventricular injection (i.c.v.) of Aß25-35 . RESULTS: Chronic administration of SV (40 mg/kg/day) for 11 days after Aß25-35 -injection ameliorated the impairment of acquisition performance and probe trail test in Morris water maze task and alternation behavior in Y maze task in Aß25-35 -mice. Aß25-35 -induced apoptosis of hippocampal CA1 pyramidal cells and Aß25-35 -impaired high-frequency stimulation (HFS)-dependent long-term potentiation (LTP) induction in hippocampal Schaffer collaterale-CA1 synapse were rescued by SV-treatment. SV prevented Aß25-35 -inhibited protein kinase B (Akt) and extracellular signal-related kinase-2 (ERK2) phosphorylation, which was sensitive to α7 nicotinic acetylcholine receptor (α7nAChR) antagonist MLA. SV-induced neuroprotection was attenuated by MLA or phosphatidylinositol-3-kinase (PI3K) antagonist LY294002. SV-rescued LTP induction was blocked by α7nAChR, PI3K or MAPK/ERK kinase (MEK) antagonist. Finally, the antiamnesia of SV in Aß25-35 -mice was attenuated by blockage of SV-induced neuroprotection or SV-rescued LTP induction. CONCLUSION: The antiamnesia of SV in Aß25-35 -mice depends on its neuroprotection and synaptic plasticity improvement.

Sigma-1 receptor knockout impairs neurogenesis in dentate gyrus of adult hippocampus via down-regulation of NMDA receptors.

AIMS: This study investigated the influence of sigma-1 receptor (σ1 R) deficiency on adult neurogenesis. METHODS: We employed 8-week-old male σ1 R knockout (σ1 R(-/-) ) mice to examine the proliferation and differentiation of progenitor cells, and the survival and neurite growth of newborn neurons in hippocampal dentate gyrus (DG). RESULTS: In comparison with wild-type (WT) littermates, the numbers of 24-h-old BrdU(+) cells and Ki67(+) cells in σ1 R(-/-) mice increased, while the number of 28-day-old BrdU(+) cells decreased without changes in proportion of BrdU(+) /NeuN(+) cells and BrdU(+) /GFAP(+) cells. The neurite density of newborn neurons was slightly reduced in σ1 R(-/-) mice. In DG granular cells, N-methyl-d-aspartate (NMDA)-activated current (INMDA ) and phosphorylation of NMDA receptor (NMDAr) NR2B were reduced in σ1 R(-/-) mice without the alteration of NR2B expression and membrane properties compared to WT mice. The NR2B antagonist abolished the difference in INMDA between σ1 R(-/-) mice and WT mice. The application of NMDAr agonist in σ1 R(-/-) mice prevented the over-proliferation of cells and reduction in newborn neurons, but it had no effects on the hypoplastic neurite. The administration of NMDAr antagonist in WT mice enhanced the cell proliferation and depressed the survival of newborn neurons. CONCLUSION: The σ1 R deficiency impairs neurogenesis in DG through down-regulation of NMDArs.

Activation of Transient Receptor Potential Vanilloid 4 Increases NMDA-Activated Current in Hippocampal Pyramidal Neurons.

The glutamate excitotoxicity, mediated through N-methyl-d-aspartate receptors (NMDARs), plays an important role in cerebral ischemia injury. Transient receptor potential vanilloid 4 (TRPV4) can be activated by multiple stimuli that may happen during stroke. The present study evaluated the effect of TRPV4 activation on NMDA-activated current (INMDA) and that of blocking TRPV4 on brain injury after focal cerebral ischemia in mice. We herein report that activation of TRPV4 by 4α-PDD and hypotonic stimulation increased INMDA in hippocampal CA1 pyramidal neurons, which was sensitive to TRPV4 antagonist 10 µ M/2 µ 1/mouse [DOSAGE ERROR CORRECTED] and NMDAR antagonist AP-5, indicating that TRPV4 activation potentiates NMDAR response. In addition, the increase in INMDA by hypotonicity was sensitive to the antagonist of NMDAR NR2B subunit, but not of NR2A subunit. Furthermore, antagonists of calcium/calmodulin-dependent protein kinase II (CaMKII) significantly attenuated hypotonicity-induced increase in INMDA, while antagonists of protein kinase C or casein kinase II had no such effect, indicating that phosphorylation of NR2B subunit by CaMKII is responsible for TRPV4-potentiated NMDAR response. Finally, we found that intracerebroventricular injection of 10 µ m/2 µ 1/mouse [DOSAGE ERROR CORRECTED] after 60 min middle cerebral artery occlusion reduced the cerebral infarction with at least a 12 h efficacious time-window. These findings indicate that activation of TRPV4 increases NMDAR function, which may facilitate glutamate excitotoxicity. Closing TRPV4 may exert potent neuroprotection against cerebral ischemia injury through many mechanisms at least including the prevention of NMDAR-mediated glutamate excitotoxicity.