97 research outputs found
Critical insights from recent outbreaks of Mycoplasma pneumoniae: decoding the challenges and effective interventions strategies
No full textOBJECTIVES: Mycoplasma pneumoniae (M. pneumoniae) continues to pose a significant disease burden on global public health as a respiratory pathogen. The antimicrobial resistance among M. pneumoniae strains has complicated the outbreak control efforts, emphasizing the need for robust surveillance systems and effective antimicrobial stewardship programs.DESIGN: This review comprehensively investigates studies stemming from previous outbreaks to emphasize the multifaceted nature of M. pneumoniae infections, encompassing epidemiological dynamics, diagnostic innovations, antibiotic resistance, and therapeutic challenges.RESULTS: We explored the spectrum of clinical manifestations associated with M. pneumoniae infections, emphasizing the continuum of disease severity and the challenges in gradating it accurately. Artificial intelligence and machine learning have emerged as promising tools in M. pneumoniae diagnostics, offering enhanced accuracy and efficiency in identifying infections. However, their integration into clinical practice presents hurdles that need to be addressed. Further, we elucidate the pivotal role of pharmacological interventions in controlling and treating M. pneumoniae infections as the efficacy of existing therapies is jeopardized by evolving resistance mechanisms.CONCLUSION: Lessons learned from previous outbreaks underscore the importance of adaptive treatment strategies and proactive management approaches. Addressing these complexities demands a holistic approach integrating advanced technologies, genomic surveillance, and adaptive clinical strategies to effectively combat this pathogen.</p
Spike timing-dependent plasticity as the origin of the formation of clustered synaptic efficacy engrams
No full textSynapse location, dendritic active properties and synaptic plasticity are all known to play some role in shaping the different input streams impinging onto a neuron. It remains unclear however, how the magnitude and spatial distribution of synaptic efficacies emerge from this interplay. Here, we investigate this interplay using a biophysically detailed neuron model of a reconstructed layer 2/3 pyramidal cell and spike timing-dependent plasticity (STDP). Specifically, we focus on the issue of how the efficacy of synapses contributed by different input streams are spatially represented in dendrites after STDP learning. We construct a simple feed forward network where a detailed model neuron receives synaptic inputs independently from multiple yet equally sized groups of afferent fibers with correlated activity, mimicking the spike activity from different neuronal populations encoding, for example, different sensory modalities. Interestingly, ensuing STDP learning, we observe that for all afferent groups, STDP leads to synaptic efficacies arranged into spatially segregated clusters effectively partitioning the dendritic tree. These segregated clusters possess a characteristic global organization in space, where they form a tessellation in which each group dominates mutually exclusive regions of the dendrite. Put simply, the dendritic imprint from different input streams left after STDP learning effectively forms what we term a "dendritic efficacy mosaic." Furthermore, we show how variations of the inputs and STDP rule affect such an organization. Our model suggests that STDP may be an important mechanism for creating a clustered plasticity engram, which shapes how different input streams are spatially represented in dendrite.Nicolangelo Libero Iannella, Thomas Launey and Shigeru Tanak
Integration of Excitatory Postsynaptic Potentials in Dendrites of Motoneurons of Rat Spinal Cord Slice Cultures
No full text Larkum, Matthew E., Thomas Launey, Alexander Dityatev, and Hans-R. Lüscher. Integration of excitatory postsynaptic potentials in dendrites of motoneurons of rat spinal cord slice cultures. J. Neurophysiol. 80: 924–935, 1998. We examined the attenuation and integration of spontaneous excitatory postsynaptic potentials (sEPSPs) in the dendrites of presumed motoneurons (MNs) of organotypic rat spinal cord cultures. Simultaneous whole cell recordings in current-clamp mode were made from either the soma and a dendrite or from two dendrites. Direct comparison of the two voltage recordings revealed that the membrane potentials at the two recording sites followed each other very closely except for the fast-rising phases of the EPSPs. The dendritic recording represented a low-pass filtered version of the somatic recording and vice versa. A computer-assisted method was developed to fit the sEPSPs with a generalized α-function for measuring their amplitudes and rise times (10–90%). The mean EPSP peak attenuation between the two recording electrodes was determined by a maximum likelihood analysis that extracted populations of similar amplitude ratios from the fitted events at each electrode. For each pair of recordings, the amplitude attenuation ratio for EPSP traveling from dendrite to soma was larger than that traveling from soma to dendrite. The linear relation between mean ln attenuation and distance between recording electrodes was used to map 1/ e attenuations into units of distance (μm). For EPSPs with typical time course traveling from the somatic to the dendritic recording electrode, the mean 1/ e attenuation corresponded to 714 μm; for EPSPs traveling in the opposite direction, the mean 1/ e attenuation corresponded to 263 μm. As predicted from cable analysis, fast EPSPs attenuated more in both the somatofugal and somatopetal direction than did slow EPSPs. For EPSPs with rise times shorter than ∼2.0 ms, the attenuation factor increased steeply. Compartmental computer modeling of the experiments with biocytin-filled and reconstructed MNs that used passive membrane properties revealed amplitude attenuation ratios of the EPSP traveling in both the somatofugal and somatopetal direction that were comparable to those observed in real experiments. The modeling of a barrage of sEPSPs further confirmed that the somato-dendritic compartments of a MN are virtually isopotential except for the fast-rising phase of EPSPs. Large, transient differences in membrane potential are locally confined to the site of EPSP generation. Comparing the modeling results with the experiments suggests that the observed attenuation ratios are adequately explained by passive membrane properties alone. </jats:p
Modulating STDP Balance Impacts the Dendritic Mosaic
No full textThe ability for cortical neurons to adapt their input/output characteristics and information processing capabilities ultimately relies on the interplay between synaptic plasticity, synapse location, and the nonlinear properties of the dendrite. Collectively, they shape both the strengths and spatial arrangements of convergent afferent inputs to neuronal dendrites. Recent experimental and theoretical studies support a clustered plasticity model, a view that synaptic plasticity promotes the formation of clusters or hotspots of synapses sharing similar properties. We have previously shown that spike timing-dependent plasticity (STDP) can lead to synaptic efficacies being arranged into spatially segregated clusters. This effectively partitions the dendritic tree into a tessellated imprint which we have called a dendritic mosaic. Here, using a biophysically detailed neuron model of a reconstructed layer 2/3 pyramidal cell and STDP learning, we investigated the impact of altered STDP balance on forming such a spatial organization. We show that cluster formation and extend depend on several factors, including the balance between potentiation and depression, the afferents' mean firing rate and crucially on the dendritic morphology. We find that STDP balance has an important role to play for this emergent mode of spatial organization since any imbalances lead to severe degradation- and in some case even destruction- of the mosaic. Our model suggests that, over a broad range of of STDP parameters, synaptic plasticity shapes the spatial arrangement of synapses, favoring the formation of clustered efficacy engrams
The Regulatory Connection between the Activity of Granule Cell NMDA Receptors and Dendritic Differentiation of Cerebellar Purkinje Cells
No full textIt is known that cerebellar granule cells are powerful inducers for the differentiation of Purkinje cells. However, the detailed mechanism of this regulation has not yet been clarified. Here, using cerebellar neuronal culture, we show that the activation of NMDA receptors expressed by granule cells triggers the signaling pathway for the dendritic differentiation of Purkinje cells. This signal has been shown to promote the granule cell survival through BDNF-mediated TrkB activation, leading to Purkinje cell differentiation by increasing the granule–Purkinje cell interaction. Among the possible signal molecules provided to the dendrites of Purkinje cells from granule cells, nitric oxide was found to have no effect on the dendritic outgrowth and branching, but electrical activity and the subsequent intracellular Ca2+increase were thought to play an important role in the branching and thickening of the dendrites, because blockade of both non-NMDA and metabotropic glutamate receptors caused a significant decrease in the number of branch points and the diameter of Purkinje dendrites without apparently affecting the dendrite extension and spine formation. Collectively, these results suggest that Purkinje cell differentiation is regulated by two successive steps. The first step is initiated by the NMDA receptor-mediated signal in granule cells, which acts as a trophic factor for granule cells. The second step involves the activation of granule–Purkinje synapses, providing neurotrophic substances and electrical activity essential for Purkinje cell differentiation.</jats:p
Modulating STDP Balance Impacts the Dendritic Mosaic
No full textThe ability for cortical neurons to adapt their input/output characteristics and information processing capabilities ultimately relies on the interplay between synaptic plasticity, synapse location, and the nonlinear properties of the dendrite. Collectively, they shape both the strengths and spatial arrangements of convergent afferent inputs to neuronal dendrites. Recent experimental and theoretical studies support a clustered plasticity model, a view that synaptic plasticity promotes the formation of clusters or hotspots of synapses sharing similar properties. We have previously shown that spike timing-dependent plasticity (STDP) can lead to synaptic efficacies being arranged into spatially segregated clusters. This effectively partitions the dendritic tree into a tessellated imprint which we have called a dendritic mosaic. Here, using a biophysically detailed neuron model of a reconstructed layer 2/3 pyramidal cell and STDP learning, we investigated the impact of altered STDP balance on forming such a spatial organization. We show that cluster formation and extend depend on several factors, including the balance between potentiation and depression, the afferents’ mean firing rate and crucially on the dendritic morphology. We find that STDP balance has an important role to play for this emergent mode of spatial organization since any imbalances lead to severe degradation- and in some case even destruction- of the mosaic. Our model suggests that, over a broad range of of STDP parameters, synaptic plasticity shapes the spatial arrangement of synapses, favoring the formation of clustered efficacy engrams
Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo.
No full textThe level of drebrin, an evolutionarily conserved f-actin-binding protein that regulates synaptic structure and function, is reduced in the brains of patients with chronic neurodegenerative diseases such as Alzheimer's disease (AD) and Down's syndrome (DS). It was suggested that excitotoxic neuronal death caused by overactivation of NMDA-type glutamate receptors (NMDARs) occurs in AD and DS; however, the relationship between excitotoxicity and drebrin loss is unknown. Here, we show that drebrin is a novel target of calpain-mediated proteolysis under excitotoxic conditions induced by the overactivation of NMDARs. In cultured rodent neurons, degradation of drebrin was confirmed by the detection of proteolytic fragments, as well as a reduction in the amount of full-length drebrin. Notably, the NMDA-induced degradation of drebrin in mature neurons occurred concomitantly with a loss of f-actin. Furthermore, pharmacological inhibition of f-actin loss facilitated the drebrin degradation, suggesting a functional linkage between f-actin and drebrin degradation. Biochemical analyses using purified drebrin and calpain revealed that calpain degraded drebrin directly in vitro. Furthermore, cerebral ischemia also induced the degradation of drebrin in vivo. These findings suggest that calpain-mediated degradation of drebrin is a fundamental pathology of neurodegenerative diseases mediated by excitotoxicity, regardless of whether they are acute or chronic. Drebrin regulates the synaptic clustering of NMDARs; therefore, degradation of drebrin under excitotoxic conditions may modulate NMDAR-mediated signal transductions, including pro-survival signaling. Overall, the results presented here provide novel insights into the molecular basis of cellular responses to excitotoxicity in vitro and in vivo
Evolutionarily conserved bias of amino-acid usage refines the definition of PDZ-binding motif
No full textAbstract Background The interactions between PDZ (PSD-95, Dlg, ZO-1) domains and PDZ-binding motifs play central roles in signal transductions within cells. Proteins with PDZ domains bind to PDZ-binding motifs almost exclusively when the motifs are located at the carboxyl (C-) terminal ends of their binding partners. However, it remains little explored whether PDZ-binding motifs show any preferential location at the C-terminal ends of proteins, at genome-level. Results Here, we examined the distribution of the type-I (x-x-S/T-x-I/L/V) or type-II (x-x-V-x-I/V) PDZ-binding motifs in proteins encoded in the genomes of five different species (human, mouse, zebrafish, fruit fly and nematode). We first established that these PDZ-binding motifs are indeed preferentially present at their C-terminal ends. Moreover, we found specific amino acid (AA) bias for the 'x' positions in the motifs at the C-terminal ends. In general, hydrophilic AAs were favored. Our genomics-based findings confirm and largely extend the results of previous interaction-based studies, allowing us to propose refined consensus sequences for all of the examined PDZ-binding motifs. An ontological analysis revealed that the refined motifs are functionally relevant since a large fraction of the proteins bearing the motif appear to be involved in signal transduction. Furthermore, co-precipitation experiments confirmed two new protein interactions predicted by our genomics-based approach. Finally, we show that influenza virus pathogenicity can be correlated with PDZ-binding motif, with high-virulence viral proteins bearing a refined PDZ-binding motif. Conclusions Our refined definition of PDZ-binding motifs should provide important clues for identifying functional PDZ-binding motifs and proteins involved in signal transduction.</p
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