Local synaptic integration of mitogen-activated protein kinase and protein kinase A signaling mediates intermediate-term synaptic facilitation in Aplysia

It is widely appreciated that memory processing engages a wide range of molecular signaling cascades in neurons, but how these cascades are temporally and spatially integrated is not well understood. To explore this important question, we used Aplysia californica as a model system. We simultaneously examined the timing and subcellular location of two signaling molecules, MAPK (ERK1/2) and protein kinase A (PKA), both of which are critical for the formation of enduring memory for sensitization. We also explored their interaction during the formation of enduring synaptic facilitation, a cellular correlate of memory, at tail sensory-to-motor neuron synapses. We find that repeated tail nerve shock (TNS, an analog of sensitizing training) immediately and persistently activates MAPK in both sensory neuron somata and synaptic neuropil. In contrast, we observe immediate PKA activation only in the synaptic neuropil. It is followed by PKA activation in both compartments 1 h after TNS. Interestingly, blocking MAPK activation during, but not after, TNS impairs PKA activation in synaptic neuropil without affecting the delayed PKA activation in sensory neuron somata. Finally, by applying inhibitors restricted to the synaptic compartment, we show that synaptic MAPK activation during TNS is required for the induction of intermediate-term synaptic facilitation, which leads to the persistent synaptic PKA activation required to maintain this facilitation. Collectively, our results elucidate how MAPK and PKA signaling cascades are spatiotemporally integrated in a single neuron to support synaptic plasticity underlying memory formation.During signal transduction, single molecules often generate different cellular effects, depending on their temporal dynamics, spatial distribution, and interacting partners (1). In considering the wide range of molecules implicated in memory processing, the question of how multiple signaling cascades are integrated in time and space to contribute to memory formation and its underlying synaptic plasticity remains a fundamental issue.We have begun to explore this general question in Aplysia californica, a model system well suited for mechanistic analyses of simple forms of learning. We focused on two molecules, MAPK (ERK1/2) and protein kinase A (PKA), both known to be engaged in many forms of memory and synaptic plasticity (2–4). Recent studies, however, suggest the timing, cellular location, and cross-talk between these kinases are critical in determining their ultimate effects (5–10). Thus, in addition to knowing that MAPK and PKA are required, it also is important to understand their spatiotemporal dynamics and their interactions during memory formation.Aplysia provides unique advantages for analyzing these questions. In Aplysia, memory for sensitization induced by tail shock (TS) is supported in large measure by synaptic facilitation at identified tail sensory-to-motor neuron (SN-MN) synapses (11). As an analog of behavioral training, tail nerve shock (TNS) also induces synaptic facilitation (12–14). A single TNS induces short-term facilitation (STF) lasting <30 min, whereas repeated spaced TNS induces intermediate-term (ITF) and long-term facilitation (LTF) lasting hours and days, respectively. TS/TNS triggers the release of serotonin (5-HT) around SN soma and SN-MN synapses, which activates a series of signaling cascades, including MAPK and cAMP/PKA (11, 12). MAPK activation is required for the formation of ITF and LTF, but not for STF, whereas cAMP/PKA is required for all three (15–18). Finally, although signaling in the synaptic compartment is critical for all forms of synaptic facilitation, it has not yet been established that MAPK and PKA can indeed be activated and exert their function locally at the SN-MN synapse. Nor is it known how they interact with each other during synaptic facilitation.In the present paper, we simultaneously examined MAPK and PKA activation in two subcellular compartments (SN soma and synaptic neuropil) at two time points (immediately and 1 h) after TNS. We found that MAPK was activated immediately and persistently in both compartments after repeated TNS. In contrast, although immediate and persistent PKA activation by repeated TNS also occurred in synaptic neuropil, we observed only delayed PKA activation in SN soma. Interestingly, MAPK activation during, but not after, TNS was essential for synaptic, but not somatic, PKA activation. Synaptic integration of these two signaling cascades in turn led to ITF. These results provide unique insights into both the spatial and temporal features of these two critical molecular cascades, and suggest a model of how they interact to regulate synaptic plasticity underlying memory formation.     

Coexistence of osteoporosis (OP) and coronary artery disease (CAD) in the elderly: it is not just a by chance event

Cardiovascular disease (CVD) and OP are common age-related conditions. In both cross-sectional and longitudinal epidemiologic studies, low bone mass has been related to increased frequency of CVD. But available data in geriatric population is limited. In this study we aimed to seek the possible relationship between CAD and low bone mineral density (BMD) in a large number of geriatric patients. A total of 2235 patients aged 65 years or more were included in this cross-sectional study. All patients underwent a complete geriatric assessment and evaluated for CAD and cardiovascular risk factors. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine (L1-L4) and femoral neck. BMD results were classified into three groups; normal (T-score: ≥-1.0×S.D.), osteopenia (T-score between -1.0 and -2.5×S.D.), and OP (T-score: ≤-2.5×S.D.). CAD was present in 397 (29.7%) of 1335 patients with OP, in 199 (27.4%) of 726 patients with osteopenia and in 34 (19.5%) of 174 patients with normal BMD. Multivariate regression analysis revealed that presence of OP or osteopenia increased the prevalence of CAD as an independent correlate (OR=1.643; 95% CI=1.068-2.528, p=0.030). This study highlights the need for careful evaluation of elderly patients with low BMD for possible CAD.     

Effects of Choukroun’s platelet-rich fibrin on bone regeneration in combination with deproteinized bovine bone mineral in maxillary sinus augmentation: A histological and histomorphometric study

PurposeThe potential effect of Choukroun’s platelet-rich fibrin (PRF) in combination with allograft on promoting bone regeneration has been discussed in previous publications. This study aims to evaluate an influence of PRF on bone regeneration in sinus augmentation in combination with a xenograft, deproteinised bovine bone.Materials and methodsEleven sinuses from 10 patients with posterior maxillary bone atrophy were selected for the study. As a test group, six sinus floor elevations were grafted with a Bio-Oss and PRF mixture, and as control group, five sinuses were treated with Bio-Oss alone. Clinical and radiographic examinations were performed pre- and postoperatively. After 6 months of sinus augmentation, bone biopsies were obtained from the grafted posterior maxilla, and un-decalcified ground sections were prepared. Bone characteristics were evaluated using histological observation and histomorphometric analyses.ResultsNo adverse effect was observed in any case within the follow-up period of 6 months after sinus augmentation. Histological observation showed similar morphological characteristics for both the PRF and control groups. The percentage of new bone formation in the PRF group was about 1.4 times of that in control (18.35% ± 5.62% vs. 12.95% ± 5.33%), while the percentage of residual bone substitute in the control group was about 1.5 times higher as that in the PRF group (28.54% ± 12.01% vs. 19.16% ± 6.89%). The percentage of contact length between newly formed bone and bone substitute in the PRF group was 21.45% ± 14.57% vs. 18.57% ± 5.39% in the control. No significant statistical differences between the two groups were found in these observed parameters.ConclusionsOur preliminary result demonstrated neither an advantage nor disadvantage of the application of PRF in combination with deproteinised bovine bone mineral in sinus augmentation after a healing period of 6 months.     

纤维分体桩高嵌体修复低牙合龈距后牙残冠的临床评价

目的:评价含有纤维分体桩的钴铬合金烤瓷高嵌体以及二氧化锆全瓷高嵌体修复低龈距后牙残冠的临床效果。方法:用含纤维分体桩的钴铬合金烤瓷高嵌体、二氧化锆全瓷高嵌体以及金合金分体桩高嵌体修复低龈距后牙残冠90个,修复后2周、6个月、24个月随访,对解剖形态、边缘适合性、边缘着色、表面质地、继发龋等临床修复效果进行评价。结果:3种分体桩高嵌体之间以及每种分体桩高嵌体于修复后2周、6个月、24个月之间在各评价项目上均无明显统计学差异(P≥0.05)。结论:应用含纤维分体桩的钴铬合金烤瓷高嵌体及二氧化锆全瓷高嵌体对低龈距后牙残冠进行修复,可获得与金合金分体桩高嵌体一样良好的临床修复效果;而且烤瓷和全瓷高嵌体更加美观,可适应不同层次的修复需求。     

双膦酸盐相关性颌骨坏死1例报告及文献复习

双膦酸盐类药物被广泛用于治疗骨质疏松、恶性肿瘤骨转移等相关的骨骼疾病,引起颌骨骨坏死是其严重的并发症。这种并发症或自然发生,或发生于简单牙槽外科手术后。本文报告1例静脉使用双膦酸盐类药物唑来膦酸(zoledronic acid)致上颌骨骨坏死病例,并结合文献,对双膦酸盐相关性颌骨坏死的发病机制、临床表现、预防和治疗进行讨论。