Experience-dependent synapse remodeling is associated with information storage in the nervous system. Neuronal synapses show alteration in various neurological and cognitive disorders in their structure and function. At the ultrastructural level, parallel fiber boutons contacting multiple spines of Purkinje cells in the cerebellar cortex are commonly observed in physiologically enriched animals as well as pathological ataxic mutants. However, the dendritic origin of those spines on parallel fiber multiple-synapse boutons (MSBs) has been poorly understood. Here, we investigated this issue by 3-dimensional ultrastructural analysis to determine synaptic connectivity of MSBs in both mice housed in physically enriched environment and cerebellar ataxic mutants. Our results demonstrated that environmental enrichment selectively induced MSBs to contact spines from the same parent dendrite, indicating focal strengthening of synapse through the simultaneous activation of two adjacent spines. In contrast, ataxic mutants displaying impaired motor coordination had significantly more MSBs involving spines originating from different neighboring dendrites compared to both wild-type and environmentally enriched animals, suggesting that compromising multiple synapse formation may lead to abnormal motor behavior in the mutant mice. These findings propose that environmental stimulation in normal animals mainly involves the refinement of preexisting synaptic networks, whereas pathological ataxic conditions may results from less-selective but compromising multiple synaptic formation. This study underscores that different types of multiple synapse boutons may have disparate effects on cerebellar synaptic transmission.

Background The purpose of our study was to assess the use of opioids before and after hip fracture in elderly patients in order to determine the effect of opioid use on all-cause mortality, and to analyze how the history of opioid use before fracture increases the risk of sustained use following hip fracture using a Korea nationwide cohort. Methods Our study identified hip fracture patients from the Korean National Health Insurance Service-Senior cohort. The index date was defined as 90-days after admission to the acute care hospital that fulfilled the eligibility criteria of elderly hip fracture. Patients were classified into past user, current user, and sustained user according to the use of opioid at each period based on the time of admission and index date. The opioids were classified into strong opioids and tramadol. A generalized estimating equation model with a Poisson distribution and logarithmic link function was performed to estimate the adjusted rate ratios (aRRs) and 95% confidence intervals (CIs) to assess the association between past use and sustained use. A multivariable-adjusted Cox proportional hazard model was used to investigate the effects of strong opioid and tramadol use on all-cause mortality. Results A total of 12,927 patients were included in our study. There were 7,384 (57.12%) opioid past-users, 11,467 (88.71%) opioid current-users, and 7,172 (55.48%) sustained users. In comparison of the death risk according to current use or the defined daily dose of the opioids or past opioid use, there were no significant differences in the adjusted hazard ratio for death in all groups, compared to the current non-users ( P > 0.05). Among survivors 1 year after hip fracture, opioid past-use increased the risk of opioid sustained use by 1.52-fold (aRR; 95% CI, 1.45–1.8; P < 0.001). Conclusion Current use and past use of opioid did not increase all-cause mortality after hip fracture in elderly patients over 65 years of age. Past use of opioid before hip fracture increased risk of sustained use of opioid compared to the current opioid used without past use.