Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAP

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66364/1/j.1471-4159.2008.05335.x.pd

Presynaptically Released Cbln1 Induces Dynamic Axonal Structural Changes by Interacting with GluD2 during Cerebellar Synapse Formation

SummaryDifferentiation of pre- and postsynaptic sites is coordinated by reciprocal interaction across synaptic clefts. At parallel fiber (PF)-Purkinje cell (PC) synapses, dendritic spines are autonomously formed without PF influence. However, little is known about how presynaptic structural changes are induced and how they lead to differentiation of mature synapses. Here, we show that Cbln1 released from PFs induces dynamic structural changes in PFs by a mechanism that depends on postsynaptic glutamate receptor delta2 (GluD2) and presynaptic neurexin (Nrx). Time-lapse imaging in organotypic culture and ultrastructural analyses in vivo revealed that Nrx-Cbln1-GluD2 signaling induces PF protrusions that often formed circular structures and encapsulated PC spines. Such structural changes in PFs were associated with the accumulation of synaptic vesicles and GluD2, leading to formation of mature synapses. Thus, PF protrusions triggered by Nrx-Cbln1-GluD2 signaling may promote bidirectional maturation of PF-PC synapses by a positive feedback mechanism

Reciprocal interaction with G-actin and tropomyosin is essential for aquaporin-2 trafficking

Trafficking of water channel aquaporin-2 (AQP2) to the apical membrane and its vasopressin and protein kinase A (PKA)–dependent regulation in renal collecting ducts is critical for body water homeostasis. We previously identified an AQP2 binding protein complex including actin and tropomyosin-5b (TM5b). We show that dynamic interactions between AQP2 and the actin cytoskeleton are critical for initiating AQP2 apical targeting. Specific binding of AQP2 to G-actin in reconstituted liposomes is negatively regulated by PKA phosphorylation. Dual color fluorescence cross-correlation spectroscopy reveals local AQP2 interaction with G-actin in live epithelial cells at single-molecule resolution. Cyclic adenosine monophosphate signaling and AQP2 phosphorylation release AQP2 from G-actin. In turn, AQP2 phosphorylation increases its affinity to TM5b, resulting in reduction of TM5b bound to F-actin, subsequently inducing F-actin destabilization. RNA interference–mediated knockdown and overexpression of TM5b confirm its inhibitory role in apical trafficking of AQP2. These findings indicate a novel mechanism of channel protein trafficking, in which the channel protein itself critically regulates local actin reorganization to initiate its movement

Hippocampal Synaptic Plasticity in Mice Overexpressing an Embryonic Subunit of the NMDA Receptor

The effects of changing NMDA receptor subunit composition on synaptic plasticity in the hippocampus were analyzed by creating transgenic mice overexpressing NR2D, a predominantly embryonic NMDA receptor subunit. NMDA-evoked currents in the transgenic mice had smaller amplitudes and slower kinetics. The transgenics also displayed age-dependent deficits in synaptic plasticity in area CA1 of the hippocampus. Long-term depression was selectively impaired in juvenile mice when NR2D overexpression was moderate. In mature mice, overexpression of NR2D was associated with a reduction of both NR2B and Ca^(2+)-independent activity of Ca^(2+)- and calmodulin-dependent protein kinase II. These biochemical changes were correlated with a marked impairment of NMDA-dependent long-term potentiation, but spatial behavior was normal in these mice. These results show that the developmental regulation of NMDA receptor subunit composition alters the frequency at which modification of synaptic responses occur after afferent stimulation

Comparative Outcomes of Laparoscopic Gastrectomy and Open Gastrectomy for Scirrhous Gastric Cancer: A Multicenter Retrospective Cohort Study

Objective: A multicenter retrospective cohort study was performed to compare the outcomes of laparoscopic gastrectomy (LG) versus open gastrectomy (OG) for scirrhous gastric cancer (GC) as a unique subtype also known as type 4 gastric cancer or linitis plastica. Background: Although data on the efficacy and safety of LG as an alternative to OG are emerging, the applicability of LG to scirrhous GC remains unclear. Methods: Patients with clinical type 4 GC undergoing gastrectomy at 13 hospitals from 2005 to 2015 were retrospectively reviewed. As the primary endpoint, we compared overall survival (OS) between the LG and OG groups. To adjust for confounding factors, we used multivariate Cox regression analysis for the main analyses and propensity-score matching for sensitivity analysis. Short-term outcomes and recurrence-free survival were also compared. Results: A total of 288 patients (LG, 62; OG, 226) were included in the main analysis. Postoperative complications occurred in 25.8% and 30.1%, respectively (P = 0.44). No significant difference in recurrence-free survival was observed (P = 0.72). The 5-year OS rates were 32.4% and 31.6% in the LG and OG groups, respectively (P = 0.60). The hazard ratio (LG/OG) for OS was 0.98 (95% confidence interval [CI], 0.65–1.43) in the multivariate regression analysis. In the sensitivity analyses after propensity-score matching, the hazard ratio for OS was 0.92 (95% CI, 0.58–1.45). Conclusions: Considering the hazard ratios and 95% CIs for OS, LG for scirrhous GC was not associated with worse survival than that for OG

Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice

社会性の発達を調節する新たな機構を発見. 京都大学プレスリリース. 2021-03-26.Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality

Inward or Outward Costophrenic Angles: A Simple Sign on Chest X-ray for the Screening of Metabolic Syndrome

Prevention of cardiovascular diseases is a top-priority issue in Japan. To this end, we have developed a new screening method for metabolic syndrome (MetS) using chest X-ray. We recruited 200 patients who visited our outpatient cardiology clinic from March 2014 to August 2014. Patients with severe lung disease, acute coronary syndrome, and end-stage renal failure were excluded. We collected data on each patient\u27s medical history, laboratory results, waist circumference (WC), body weight, and height. Additionally, we measured two parameters from the chest X-ray: (A) width at the level of right dome of diaphragm and (B) width between the costophrenic (CP) angles. We classified the CP angles as either inward (A≥B) or outward (A<B). Increased WC was defined as ≥85cm in males and ≥90cm in females. Patients with outward CP angles had a significantly larger WC compared to those with inward CP angles (92.3±8.9 vs. 80.5±7.8cm, P<0.001). In particular, the percentage of male patients with increased WC (≥ 85cm) was significantly higher in patients with outward CP angles than in those with inward CP angles (89.2% vs. 41.3%, P<0.001). Body weight and BMI were both significantly higher in patients with outward CP angles than in those with inward CP angles in both gender groups. When laboratory data and risk factors were compared, patients with outward CP angles and those with positive WC criteria consistently tended toward high morbidity from hypertension, dyslipidemia, and diabetes. The inward/outward CP identified candidates for MetS, especially in the male subjects. Chest X-ray could become a useful screening tool for the detection of increased WC and coronary risk factors