title: Mitochondrial regulation of synaptic plasticity in the hippocampus.
abstract: Synaptic mechanisms of plasticity are calcium-dependent processes that are affected by dysfunction of mitochondrial calcium buffering. Recently, we observed that mice deficient in mitochondrial voltage-dependent anion channels, the outer component of the mitochondrial permeability transition pore, have impairments in learning and hippocampal synaptic plasticity, suggesting that the mitochondrial permeability transition pore is involved in hippocampal synaptic plasticity. In this study, we examined the effect on synaptic transmission and plasticity of blocking the permeability transition pore with low doses of cyclosporin A and found a deficit in synaptic plasticity and an increase in base-line synaptic transmission. Calcium imaging of presynaptic terminals revealed a transient increase in the resting calcium concentration immediately upon incubation with cyclosporin A that correlated with the changes in synaptic transmission and plasticity. The effect of cyclosporin A on presynaptic calcium was abolished when mitochondria were depolarized prior to cyclosporin A exposure, and the effects of cyclosporin A and mitochondrial depolarization on presynaptic resting calcium were similar, suggesting a mitochondrial locus of action of cyclosporin A. To further characterize the calcium dynamics of the mitochondrial permeability transition pore, we used an in vitro assay of calcium handling by isolated brain mitochondria. Cyclosporin A-exposed mitochondria buffered calcium more rapidly and subsequently triggered a more rapid mitochondrial depolarization. Similarly, mitochondria lacking the voltage-dependent anion channel 1 isoform depolarized more readily than littermate controls. The data suggest a role for the mitochondrial permeability transition pore and voltage-dependent anion channels in mitochondrial synaptic calcium buffering and in hippocampal synaptic plasticity.
authors.affiliation: Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Levy
authors.forename: Guido C
authors.initials: GC
authors.lastname: Faas
authors.forename: Peter
authors.initials: P
authors.lastname: Saggau
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
mesh_terms: D000818:Animals; D000838:Anions; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D020033:Protein Isoforms; D016704:Synapsins / Q000378:metabolism; D013997:Time Factors
chemical_list: D000838:Anions; D020033:Protein Isoforms; D016704:Synapsins; D016572:Cyclosporine; D002118:Calcium