Activity-dependent subcellular compartmentalization of dendritic mitochondria structure in CA1 pyramidal neurons

Virga, Daniel M.; Hamilton, Stevie; Osei, Bertha; Morgan, Abigail; Zamponi, Emiliano; Park, Natalie J; Hewitt, Victoria L.; Zhang, David; Gonzalez, Kevin; Bloss, Erik B.; Polleux, Franck; Lewis, Tommy L.

doi:10.1101/2023.03.25.534233

Cited by 3 publications

(2 citation statements)

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“…This indicates that MCU expression is not related to the differences in mitochondrial structure across CA2 dendrites. Similar heterogeneity has also been reported in CA1 neurons (Virga et al, 2023). Recently, layer-specific activity-driven differences in AMPK and CAMKK2, which regulate fission/fusion factors, were shown to contribute to the differences in mitochondria shape, in particular for CA1 basal and proximal layers (Virga et al, 2023).…”

Section: Discussionsupporting

confidence: 86%

“…Similar heterogeneity has also been reported in CA1 neurons (Virga et al, 2023). Recently, layer-specific activity-driven differences in AMPK and CAMKK2, which regulate fission/fusion factors, were shown to contribute to the differences in mitochondria shape, in particular for CA1 basal and proximal layers (Virga et al, 2023). However, whether there are similar fission/fusion differences in CA2 dendrites given their layer-specific synaptic plasticity profiles remains to be explored.…”

Section: Discussionsupporting

confidence: 86%

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MCU-enriched dendritic mitochondria regulate plasticity in distinct hippocampal circuits

Pannoni,

Fischer,

Tarannum

et al. 2023

Preprint

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Mitochondria are dynamic organelles that are morphologically and functionally diverse across different cell types and subcellular compartments in order to meet unique energy demands. In neurons, mitochondria are critical to support synapses and synaptic plasticity. However, the mechanisms regulating mitochondria in synaptic plasticity are largely unknown. 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 CA2 distal dendrites relative to neighboring CA1 or CA3 distal dendrites, suggesting mitochondria there are molecularly distinct. However, the functional significance of this enrichment is not clear. Synapses onto CA2 distal dendrites, unlike synapses onto CA2 proximal dendrites, readily undergo long-term potentiation (LTP), but the mechanisms underlying the different plasticity profiles are unknown. Therefore, we investigated the role of MCU in regulating dendritic mitochondria and synaptic plasticity in CA2 distal dendrites. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU is required for LTP at CA2 distal dendrite synapses. Loss of LTP 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 POINTSThe mitochondrial calcium uniporter regulates plasticity selectively at synapses in CA2 distal dendrites.The MCU-cKO induced LTP deficit at synapses in CA2 distal dendrites correlates with a trending reduction in spine density.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.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 86%

MCU-enriched dendritic mitochondria regulate plasticity in distinct hippocampal circuits

Pannoni,

Fischer,

Tarannum

et al. 2023

Preprint

View full text Add to dashboard Cite

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Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons

Kochan

Malo

Jevtic

et al. 2023

Preprint

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Integration of new neurons into adult hippocampal circuits is a process coordinated by local and long-range synaptic inputs. To achieve stable integration and uniquely contribute to hippocampal function, immature neurons are endowed with a critical period of heightened synaptic plasticity, yet it remains unclear which mechanisms sustain this form of plasticity during neuronal maturation. We found that, as new neurons enter their critical period, a transient surge in fusion dynamics stabilizes elongated mitochondrial morphologies in dendrites to fuel synaptic plasticity. Conditional ablation of fusion dynamics to prevent mitochondrial elongation selectively impaired spine plasticity and synaptic potentiation, disrupting neuronal competition for stable circuit integration, ultimately leading to decreased survival. Despite profuse mitochondrial fragmentation, manipulation of competition dynamics was sufficient to restore neuronal survival, but left neurons poorly responsive to experiences at the circuit level. Thus, by enabling synaptic plasticity during the critical period, mitochondrial fusion facilitates circuit remodeling by adult-born neurons.

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Postsynaptic mitochondria are positioned to support functional diversity of dendritic spines

Thomas

Ryan

Kamasawa

et al. 2023

Preprint

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Postsynaptic mitochondria are critical to the development, plasticity, and maintenance of synaptic inputs. However, their relationship to synaptic structure and functional activity is unknown. We examined a correlative dataset from ferret visual cortex with in vivo two-photon calcium imaging of dendritic spines during visual stimulation and electron microscopy (EM) reconstructions of spine ultrastructure, investigating mitochondrial abundance near functionally- and structurally-characterized spines. Surprisingly, we found no correlation to structural measures of synaptic strength. Instead, we found that mitochondria are positioned near spines with orientation preferences that are dissimilar to the somatic preference. Additionally, we found that mitochondria are positioned near groups of spines with heterogeneous orientation preferences. For a subset of spines with a mitochondrion in the head or neck, synapses were larger and exhibited greater selectivity to visual stimuli than those without a mitochondrion. Our data suggest mitochondria are not necessarily positioned to support the energy needs of strong spines, but rather support the structurally and functionally diverse inputs innervating the basal dendrites of cortical neurons.

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Activity-dependent subcellular compartmentalization of dendritic mitochondria structure in CA1 pyramidal neurons

Cited by 3 publications

References 43 publications

MCU-enriched dendritic mitochondria regulate plasticity in distinct hippocampal circuits

MCU-enriched dendritic mitochondria regulate plasticity in distinct hippocampal circuits

Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons

Postsynaptic mitochondria are positioned to support functional diversity of dendritic spines

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