Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

Abstract

Mitochondria support synaptic transmission through production of ATP, sequestration of calcium, synthesis of glutamate, and other vital functions. Surprisingly, less than 50% of hippocampal CA1 presynaptic boutons contain mitochondria, raising the question of whether synapses without mitochondria can sustain changes in efficacy. To address this question, we analyzed synapses from postnatal day 15 (P15) and adult rat hippocampus that had undergone theta-burst stimulation to produce long-term potentiation (TBS-LTP) and compared them to control or no stimulation. At 30 and 120 min after TBS-LTP, vesicles were decreased only in presynaptic boutons that contained mitochondria at P15, and vesicle decrement was greatest in adult boutons containing mitochondria. Presynaptic mitochondrial cristae were widened, suggesting a sustained energy demand. Thus, mitochondrial proximity reflected enhanced vesicle mobilization well after potentiation reached asymptote, in parallel with the apparently silent addition of new dendritic spines at P15 or the silent enlargement of synapses in adults.DOI: http://dx.doi.org/10.7554/eLife.15275.001

The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring

“…By imaging both axonal and presynaptic mitochondria in live hippocampal neurons, we recently characterized five patterns of mitochondrial motility and distribution in axons: non-synaptic stationary (54.07 ± 2.53%) and synaptic stationary mitochondria (16.29 ± 1.66%), and motile mitochondria passing through synapses (14.77 ± 1.58%), pausing at synapses briefly (7.01 ± 1.29%) or more than 200 sec (8.30 ± 1.52%) [8]. These patterns are consistent with a previous study in cortical neurons [42], and further supported by a recent in vivo 3D electron microscopy analysis of perfusion-fixed hippocampi, where 33% of total synapses contain presynaptic mitochondria, 31% of synapses have the nearest axonal mitochondrion located at a distance less than 3 µm from the synapses, and 36% of synapses have a distance greater than 3 µm to the nearest axonal mitochondrion [49]. …”

“…These findings raise a question as to whether presynaptic mitochondria could provide more ATP sources to sustain increased synaptic efficacy. By 3D electron microscopy, the Harris group recently demonstrated that sustained synaptic activity is specific to the mitochondria-containing presynaptic boutons during long-term potentiation [49]. Presynaptic boutons with mitochondria have more docked SVs than those without mitochondria in the hippocampal CA1 area.…”

Presynaptic loss of dynamin‐related protein 1 impairs synaptic vesicle release and recycling at the mouse calyx of Held

“…; Smith et al . ; Devine & Kittler, ). Pharmacological approaches have shown that mitochondria can regulate short‐term plasticity by adjusting Ca 2+ ‐dependent neurotransmitter release and synaptic vesicle recycling, and act to fulfil bioenergetic demands of the synapse by maintaining ATP during intense synaptic activity (Alnaes & Rahamimoff, ; Tang & Zucker, ; Li et al .…”

Mechanisms for the maintenance and regulation of axonal energy supply

“…Even in hippocampal synaptosomes, inhibition of oxphos reduces ATP levels and evoked synaptic vesicle release, directly demonstrating that synaptic physiology is affected by local, mitochondrial ATP production (Ivannikov, Sugimori, & Llinas, ). By 3D EM analysis of hippocampi, the Harris group recently demonstrated that only 33% of total presynapses retain mitochondria and sustained synaptic activity is restricted to these mitochondria‐containing presynapses during long‐term potentiation (Smith, Bourne, Cao, Chirillo, & Ostroff, ). However, the mechanisms retaining and anchoring mitochondria at presynapses remain elusive.…”

“…By 3D EM analysis of hippocampi, the Harris group recently demonstrated that only 33% of total presynapses retain mitochondria and sustained synaptic activity is restricted to these mitochondria-containing presynapses during long-term potentiation (Smith, Bourne, Cao, Chirillo, & Ostroff, 2016). However, the mechanisms retaining and anchoring mitochondria at presynapses remain elusive.…”