MCU-enriched dendritic mitochondria regulate plasticity in distinct hippocampal circuits.

Mitochondria are dynamic organelles that are morphologically and functionally diverse across cell types and subcellular compartments in order to meet unique energy demands. Mitochondrial dysfunction has been implicated in a wide variety of neurological disorders, including psychiatric disorders like schizophrenia and bipolar disorder. Despite it being well known that mitochondria are essential for synaptic transmission and synaptic plasticity, the mechanisms regulating mitochondria in support of normal synapse function are incompletely understood. The mitochondrial calcium uniporter (MCU) regulates calcium entry into the mitochondria, which in turn regulates the bioenergetics and distribution of mitochondria to active synapses. Evidence suggests that calcium influx via MCU couples neuronal activity to mitochondrial metabolism and ATP production, which would allow neurons to rapidly adapt to changing energy demands. Intriguingly, MCU is uniquely enriched in hippocampal CA2 distal dendrites relative to neighboring hippocampal CA1 or CA3 distal dendrites, however, the functional significance of this enrichment is not clear. Synapses from the entorhinal cortex layer II (ECII) onto CA2 distal dendrites readily express long term potentiation (LTP), unlike the LTP- resistant synapses from CA3 onto CA2 proximal dendrites, but the mechanisms underlying these different plasticity profiles are unknown. We hypothesized that enrichment of MCU near ECII-CA2 synapses promotes LTP in an otherwise plasticity-restricted cell type. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU is required for LTP at distal dendrite synapses but does not affect the lack of LTP at proximal dendrite synapses. Loss of LTP at ECII-CA2 synapses correlated with a trend for decreased spine density in CA2 distal dendrites of cKO mice compared to control (CTL) mice, which was predominantly seen in immature spines. Moreover, mitochondria were significantly smaller and more numerous across all dendritic layers of CA2 in cKO mice compared to CTL mice, suggesting an overall increase in mitochondrial fragmentation. Fragmented mitochondria might have functional changes, such as altered ATP production, that might explain a deficit in synaptic plasticity. Collectively, our data reveal that MCU regulates layer-specific forms of plasticity in CA2 dendrites, potentially by maintaining proper mitochondria morphology and distribution within dendrites. Differences in MCU expression across different cell types and circuits might be a general mechanism to tune the sensitivity of mitochondria to cytoplasmic calcium levels to power synaptic plasticity. MAIN TAKE HOME POINTS: The mitochondrial calcium uniporter (MCU) regulates plasticity selectively at synapses in CA2 distal dendrites.The MCU-cKO induced LTP deficit correlates with a trending reduction in spine density in CA2 distal dendrites.Loss of MCU in CA2 results in ultrastructural changes in dendritic mitochondria that suggest an increase in mitochondrial fragmentation. These ultrastructural changes could result in functional consequences, such as decreased ATP production, that could underlie the plasticity deficit.Dendritic mitochondrial fragmentation in MCU cKO occurred throughout the dendritic laminae, suggesting that MCU is dispensable for establishing layer-specific mitochondrial structural diversity.

Cost of primary care approaches for hypertension management and risk-based cardiovascular disease prevention in Bangladesh: a HEARTS costing tool application.

OBJECTIVE: To estimate the costs of scaling up the HEARTS pilot project for hypertension management and risk-based cardiovascular disease (CVD) prevention at the full population level in the four subdistricts (upazilas) in Bangladesh. SETTINGS: Two intervention scenarios in subdistrict health complexes: hypertension management only, and risk-based integrated hypertension, diabetes, and cholesterol management. DESIGN: Data obtained during July-August 2020 from subdistrict health complexes on the cost of medications, diagnostic materials, staff salaries and other programme components. METHODS: Programme costs were assessed using the HEARTS costing tool, an Excel-based instrument to collect, track and evaluate the incremental annual costs of implementing the HEARTS programme from the health system perspective. PRIMARY AND SECONDARY OUTCOME MEASURES: Programme cost, provider time. RESULTS: The total annual cost for the hypertension control programme was estimated at US$3.2 million, equivalent to US$2.8 per capita or US$8.9 per eligible patient. The largest cost share (US$1.35 million; 43%) was attributed to the cost of medications, followed by the cost of provider time to administer treatment (38%). The total annual cost of the risk-based integrated management programme was projected at US$14.4 million, entailing US$12.9 per capita or US$40.2 per eligible patient. The estimated annual costs per patient treated with medications for hypertension, diabetes and cholesterol were US$18, US$29 and US$37, respectively. CONCLUSION: Expanding the HEARTS hypertension management and CVD prevention programme to provide services to the entire eligible population in the catchment area may face constraints in physician capacity. A task-sharing model involving shifting of select tasks from doctors to nurses and local community health workers would be essential for the eventual scale-up of primary care services to prevent CVD in Bangladesh.