It has long been hypothesized that changes in dendritic spine structure may modify the physiological properties of synapses located on them. Due to their small size, large number, and highly variable shapes, standard light microscopy of Golgi impregnations and electron microscopy (EM) of single thin sections have not proved adequate to identify most spines in a sample or to quantify their structural dimensions and composition. Here we describe a new approach, the series sample, that was developed to classify by shape and subcellular composition all of the spines and synapses in a sample of neuropil by viewing them through serial EM sections. Spines in each class are then randomly selected for serial reconstruction and measurement in three dimensions. This approach was used to assess whether structural changes in hippocampal CA1 spines could contribute to the enhanced synaptic transmission and the greater endurance of long-term potentiation (LTP) that occur with maturation. Our results show a near doubling in the total density of synapses in the neuropil and along reconstructed dendrites between postnatal day 15 (PND 15) and adult ages. However, this doubling does not occur uniformly across all spine and synapse morphologies. Thin spines, mushroom spines containing perforated postsynaptic densities (PSDs) and spine apparatuses, and branched spines increase by about four-fold in density between PND 15 and adult ages. In contrast, stubby spines decrease by more than half and no change occurs in mushroom spines with macular PSDs or in dendritic shaft synapses. The stubby spines that remain are smaller in adults than at PND 15 and the mushroom spines are larger, while no change occurs in the three-dimensional structure of thin spines. Only a few spine necks at either age are constricted or long enough to attenuate charge transfer; therefore, the doubling in synapses should mediate the enhancement of synaptic transmission that occurs with maturation. In addition, LTP is not likely to be mediated by widening of spine necks at either age. However, the constricted spine necks could serve to concentrate specific molecules at activated synapses, thereby enhancing the specificity and endurance of LTP with maturation. These results demonstrate that the new series sample method combined with three- dimensional reconstruction reveals quantitative changes in the frequency and structure of spines and synapses that are not discernable by other methods and are likely to have dramatic effects on synaptic physiology and plasticity.
We have used serial electron microscopy and 3-dimensional reconstructions of dendritic spines from Purkinje spiny branchlets of normal adult rats to evaluate 2 questions about the relationship of spine geometry to synaptic efficacy. First, do relationships between spine geometry and other anatomical indicators of synaptic activity suggest that spine size and shape might be associated with synaptic efficacy? Reconstructed spines were graphically edited into head and neck compartments; the area of the postsynaptic density (PSD) was measured; the volume of spine smooth endoplasmic reticulum (SER) was computed; and all of the vesicles in the axonal varicosities were counted. Spine head volume and the volume of SER contained in the head are well correlated with the area of the PSD and the number of vesicles in the presynaptic axonal varicosity. Spine neck diameter does not fluctuate with PSD area, head volume, or the vesicle number. These results suggest that the dimensions of the spine head, but not of the spine neck, are likely to reflect differences in synaptic efficacy. Second, does the geometry of cerebellar spine necks reduce the transfer of synaptic charge to the recipient dendrite from the theoretical maximum that could be transferred if the synapse were on a dendritic shaft? Comparison of volume to surface area showed that the spine heads are approximately spherical and the necks are approximately cylindrical. Application of results from a biophysical model that assumed these geometrical shapes for spines (Wilson, 1984) showed that the cerebellar spine necks are unlikely to reduce transfer of synaptic charge by more than 5-20% even if their SER were to completely block passage of current through the portion of the neck that it occupies. We suggest that the constricted spine neck diameter might serve to isolate metabolic events in the vicinity of activated synapses by reducing diffusion to neighboring synapses, without significantly influencing the transfer of synaptic charge to the postsynaptic dendrite.
AimsAsthma exacerbations peak in school-aged children following the autumn school return. Modifiable factors, including poor treatment adherence during the summer months and increased allergen and viral exposure may underlie these observations. Interventions implemented in anticipation of the autumn school return might lessen the burden upon patients and healthcare resources. We undertook a Cochrane systematic review to assess the effectiveness of interventions aiming to reduce asthma exacerbations in children returning to school.MethodsRandomised controlled trials (RCTs) were identified in searches of the Cochrane Airways Group Specialised Register (CAGR) and other supplementary sources. Eligibility criteria included study design (RCTs), intervention (intended to reduce autumn exacerbations) and population (participants aged 18 years or younger). We appraised the quality of trials using the Cochrane Risk of Bias tool.Results520 records were retrieved. 4 studies met the inclusion criteria and together randomised 14 048 children to receive an intervention or usual care. Two studies employed the leukotriene receptor antagonist (LTRA) montelukast, one used omalizumab or an inhaled corticosteroids boost and the last analysed the impact of a reminder letter sent to caregivers from Primary Care Providers about asthma medication. Quality ratings in most domains were low risk.Risk of exacerbation were significantly reduced in single studies of omalizumab OR 0.48 (95% CI: 0.25 to 0.92) and montelukast OR 0.25 (0.08–0.79). Frequency of unscheduled contacts increased during September (OR 1.30 95% CI: 1.03 to 1.66) due to the reminder correspondence. The incidence of adverse events did not differ between trial arms. An updated search retrieved 25 further studies, including a randomised open trial of pranlukast. This un-blinded study was of poorer quality, relying largely upon subjective outcomes. Pranlukast was found to be superior to usual care in reducing worsening asthma symptoms only in boys aged 1–5 years.ConclusionOmalizumab treatment initiated 4–6 weeks in advance of the school return might reduce autumn asthma exacerbations. This review identified a need for coordinated research employing validated measurement tools to explore patient-important outcomes including the impact of interventions on asthma control or quality of life. We would recommend that exacerbation definition be standardised in future trials.
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