Abstract
The structure and function of neurons is dynamic during development and in adaptive responses of the adult nervous system to environmental demands. The mechanisms that regulate neuronal plasticity are poorly understood, but are believed to involve neurotransmitter and neurotrophic factor signaling pathways. In the present article, I review emerging evidence that mitochondria play important roles in regulating developmental and adult neuroplasticity. In neurons, mitochondria are located in axons, dendrites, growth cones and pre- and post-synaptic terminals where their movements and functions are regulated by local signals such as neurotrophic factors and calcium influx. Mitochondria play important roles in fundamental developmental processes including the establishment of axonal polarity and the regulation of neurite outgrowth, and are also involved in synaptic plasticity in the mature nervous system. Abnormalities in mitochondria are associated with neurodegenerative and psychiatric disorders, suggesting a therapeutic potential for approaches that target mitochondrial mechanisms.
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References
Charron F, Tessier-Lavigne M (2005) Novel brain wiring functions for classical morphogens: a role as graded positional cues in axon guidance. Development 132:2251–2262
Yuste R, Bonhoeffer T (2001) Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 24:1071–1089
Wong RO, Ghosh A (2002) Activity-dependent regulation of dendritic growth and patterning. Nat Rev Neurosci 3:803–812
Carlisle HJ, Kennedy MB (2005) Spine architecture and synaptic plasticity. Trends Neurosci 28:182–187
Henley J, Poo MM (2004) Guiding neuronal growth cones using Ca2+ signals. Trends Cell Biol 14:320–330
Oertner TG, Matus A (2005) Calcium regulation of actin dynamics in dendritic spines. Cell Calcium 37:477–482
Simpson PB (2000) The local control of cytosolic Ca2+ as a propagator of CNS communication–integration of mitochondrial transport mechanisms and cellular responses. J Bioenerg Biomembr 32:5–13
Chan SL, Fu W, Zhang P, Cheng A, Lee J, Kokame K, Mattson MP (2004) Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress. J Biol Chem 279:28733–28743
Mironov SL, Ivannikov MV, Johansson M (2005) [Ca2+]i signaling between mitochondria and endoplasmic reticulum in neurons is regulated by microtubules. From mitochondrial permeability transition pore to Ca2+-induced Ca2+ release. J Biol Chem 280:715–721
Morris RL, Hollenbeck PJ (1995) Axonal transport of mitochondria along microtubules and F-actin in living vertebrate neurons. J Cell Biol 131:1315–1326
Suzuki YJ, Forman HJ, Sevanian A (1997) Oxidants as stimulators of signal transduction. Free Radic Biol Med 22:269–285
Hongpaisan J, Winters CA, Andrews SB (2004) Strong calcium entry activates mitochondrial superoxide generation, upregulating kinase signaling in hippocampal neurons. J Neurosci 24:10878–10887
Kamsler A, Segal M (2003) Paradoxical actions of hydrogen peroxide on long-term potentiation in transgenic superoxide dismutase-1 mice. J Neurosci 23:10359–10367
Mattson MP, Kroemer G (2003) Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol Med 9:196–205
Jonas EA, Hardwick JM, Kaczmarek LK (2005a) Actions of BAX on mitochondrial channel activity and on synaptic transmission. Antioxid Redox Signal 7:1092–1100
Glazner GW, Chan SL, Lu C, Mattson MP (2000) Caspase-mediated degradation of AMPA receptor subunits: a mechanism for preventing excitotoxic necrosis and ensuring apoptosis. J Neurosci 20:3641–3649
Lu C, Fu W, Salvesen GS, Mattson MP (2002) Direct cleavage of AMPA receptor subunit GluR1 and suppression of AMPA currents by caspase-3: implications for synaptic plasticity and excitotoxic neuronal death. Neuromolecular Med 1:69–79
Lu C, Wang Y, Furukawa K, Fu W, Ouyang X, Mattson MP (2006) Evidence that caspase-1 is a negative regulator of AMPA receptor-mediated long-term potentiation at hippocampal synapses. J Neurochem 97:1104–1110
Mattson MP, Partin J (1999) Evidence for mitochondrial control of neuronal polarity. J Neurosci Res 56:8–20
Dedov VN, Armati PJ, Roufogalis BD (2000) Three-dimensional organisation of mitochondrial clusters in regenerating dorsal root ganglion (DRG) neurons from neonatal rats: evidence for mobile mitochondrial pools. J Peripher Nerv Syst 5:3–10
Ruthel G, Hollenbeck PJ (2003) Response of mitochondrial traffic to axon determination and differential branch growth. J Neurosci 23:8618–8624
Vayssiere JL, Cordeau-Lossouarn L, Larcher JC, Basseville M, Gros F, Croizat B (1992) Participation of the mitochondrial genome in the differentiation of neuroblastoma cells. In Vitro Cell Dev Biol 28A:763–772
Chada SR, Hollenbeck PJ (2004) Nerve growth factor signaling regulates motility and docking of axonal mitochondria. Curr Biol 14:1272–1276
Lee CW, Peng HB (2006) Mitochondrial clustering at the vertebrate neuromuscular junction during presynaptic differentiation. J Neurobiol 66:522–536
Cheresharov L, Ovtscharoff W, Manolov S (1978) Ultrastructural changes in the anterior horn synapses of rat spinal cord under different locomotor conditions. J Neural Transm 42:9–21
Marciniak M (1983) Morphometric ultrastructural evaluation of the axonal endings in the neuromuscular junctions of pigeons after long lasting limitation of movement. Exp Pathol 23:27–34
Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873–887
Yang F, He XP, Russell J, Lu B (2003) Ca2+ influx-independent synaptic potentiation mediated by mitochondrial Na(+)-Ca2+ exchanger and protein kinase C. J Cell Biol 163:511–523
Belair EL, Vallee J, Robitaille R (2005) Long-term in vivo modulation of synaptic efficacy at the neuromuscular junction of Rana pipiens frogs. J Physiol 569:163–178
Tang Y, Zucker RS (1997) Mitochondrial involvement in post-tetanic potentiation of synaptic transmission. Neuron 18:483–491
Calabresi P, Gubellini P, Picconi B, Centonze D, Pisani A, Bonsi P, Greengard P, Hipskind RA, Borrelli E, Bernardi G (2001) Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine. J Neurosci 21:5110–5120
Levy M, Faas GC, Saggau P, Craigen WJ, Sweatt JD (2003) Mitochondrial regulation of synaptic plasticity in the hippocampus. J Biol Chem 278:17727–17734
Weeber EJ, Levy M, Sampson MJ, Anflous K, Armstrong DL, Brown SE, Sweatt JD, Craigen WJ (2002) The role of mitochondrial porins and the permeability transition pore in learning and synaptic plasticity. J Biol Chem 277:18891–18897
Gulyaeva NV, Kudryashov IE, Kudryashova IV (2003) Caspase activity is essential for long-term potentiation. J Neurosci Res 73:853–864
Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH (2003) Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat Cell Biol 5:1051–1061
Frick KM, Fernandez SM (2003) Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiol Aging 24:615–626
Mattson MP (2005) Energy intake, meal frequency, and health: a neurobiological perspective. Annu Rev Nutr 25:237–260
van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680–8685
Briones TL, Suh E, Jozsa L, Rogozinska M, Woods J, Wadowska M (2005) Changes in number of synapses and mitochondria in presynaptic terminals in the dentate gyrus following cerebral ischemia and rehabilitation training. Brain Res 1033:51–57
Lores-Arnaiz S, Bustamante J, Arismendi M, Vilas S, Paglia N, Basso N, Capani F, Coirini H, Costa JJ, Arnaiz MR (2006) Extensive enriched environments protect old rats from the aging dependent impairment of spatial cognition, synaptic plasticity and nitric oxide production. Behav Brain Res 169:294–302
Gabbita SP, Butterfield DA, Hensley K, Shaw W, Carney JM (1997) Aging and caloric restriction affect mitochondrial respiration and lipid membrane status: an electron paramagnetic resonance investigation. Free Radic Biol Med 23:191–201
Sanz A, Caro P, Ibanez J, Gomez J, Gredilla R, Barja G (2005) Dietary restriction at old age lowers mitochondrial oxygen radical production and leak at complex I and oxidative DNA damage in rat brain. J Bioenerg Biomembr 37:83–90
Williams JM, Thompson VL, Mason-Parker SE, Abraham WC, Tate WP (1998) Synaptic activity-dependent modulation of mitochondrial gene expression in the rat hippocampus. Mol Brain Res 60:50–56
Liu D, Chan SL, de Souza-Pinto NC, Slevin JR, Wersto RP, Zhan M, Mustafa K, de Cabo R, Mattson MP (2006) Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. Neuromolecular Med 8:389–413
Ryu H, Lee J, Impey S, Ratan RR, Ferrante RJ (2005) Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons. Proc Natl Acad Sci USA 102:13915–13920
Mattson MP, Lovell M, Furukawa K, Markesbery WR (1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J Neurochem 65:1740–1751
Trenkner E, el Idrissi A, Harris C (1996) Balanced interaction of growth factors and taurine regulate energy metabolism, neuronal survival, and function of cultured mouse cerebellar cells under depolarizing conditions. Adv Exp Med Biol 403:507–517
Impey S, Obrietan K, Wong ST, Poser S, Yano S, Wayman G, Deloulme JC, Chan G, Storm DR (1998) Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21:869–883
Roberson ED, English JD, Adams JP, Selcher JC, Kondriatick C, Sweatt JD (1999) The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J Neurosci 19:4337–4348
Mattson MP, Meffert MK, (2006) Roles for NF-κB in nerve cell survival, plasticity and disease. Cell Death Differ 13:852–860
Schuchmann S, Buchheim K, Heinemann U, Hosten N, Buttgereit F (2005) Oxygen consumption and mitochondrial membrane potential indicate developmental adaptation in energy metabolism of rat cortical neurons. Eur J Neurosci 21:2721–2732
Jekabsons MB, Nicholls DG (2004) In situ respiration and bioenergetic status of mitochondria in primary cerebellar granule neuronal cultures exposed continuously to glutamate. J Biol Chem 279:32989–33000
Pardo B, Contreras L, Serrano A, Ramos M, Kobayashi K, Iijima M, Sheki T, Satrusteui J (2006) Essential role of aralar in the transduction of small Ca2+ signals to neuronal mitochondria. J Biol Chem 281:1039–1047
Markham A, Cameron I, Franklin P, Spedding M (2004) BDNF increases rat brain mitochondrial respiratory coupling at complex I, but not complex II. Eur J Neurosci 20:1189–1196
Mattson MP, Murrain M, Guthrie PB, Kater SB (1989) Fibroblast growth factor and glutamate: opposing actions in the generation and degeneration of hippocampal neuroarchitecture. J Neurosci 9:3728–3740
Cheng A, Wang S, Cai J, Rao MS, Mattson MP (2003) Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev Biol 258:319–333
Cheng B, Mattson MP (1991) NGF and bFGF protect rat and human central neurons against hypoglycemic damage by stabilizing calcium homeostasis. Neuron 7:1031–1041
Cheng B, Mattson MP (1992) IGF-I and IGF-II protect cultured hippocampal and septal neurons against calcium-mediated hypoglycemic damage. J Neurosci 12:1558–1566
Cheng B, Mattson MP, (1994) NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res 640:56–67
El Idrissi A, Trenkner E (1999) Growth factors and taurine protect against excitotoxicity by stabilizing calcium homeostasis and energy metabolism. J Neurosci 19:9459–9468
Burkhalter J, Fiumelli H, Allaman I, Chatton JY, Martin JL (2003) Brain-derived neurotrophic factor stimulates energy metabolism in developing cortical neurons. J Neurosci 23:8212–8220
Martorell L, Segues T, Folch G, Valero J, Joven J, Labad A, Vilella E (2006) New variants in the mitochondrial genomes of schizophrenic patients. Eur J Hum Genet 14:520–528
Rojo A, Campos Y, Sanchez JM, Bonaventura I, Aguilar M, Garcia A, Gonzalez L, Rey MJ, Arenas J, Olive M, Ferrer I (2006) NARP-MILS syndrome caused by 8993 T > G mitochondrial DNA mutation: a clinical, genetic and neuropathological study. Acta Neuropathol (Berl) 111:610–616
Nikali K, Suomalainen A, Saharinen J, Kuokkanen M, Spelbrink JN, Lonnqvist T, Peltonen L (2005) Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet 14:2981–2990
Schon EA, Santra S, Pallotti F, Girvin ME (2001) Pathogenesis of primary defects in mitochondrial ATP synthesis. Semin Cell Dev Biol 12:441–448
Boles RG, Burnett BB, Gleditsch K, Wong S, Guedalia A, Kaariainen A, Eloed J, Stern A, Brumm V (2005) A high predisposition to depression and anxiety in mothers and other matrilineal relatives of children with presumed maternally inherited mitochondrial disorders. Am J Med Genet B Neuropsychiatr Genet 137:20–24
Blass JP (2000) The mitochondrial spiral. An adequate cause of dementia in the Alzheimer’s syndrome. Ann NY Acad Sci 924:170–183
Chan PH (2004) Mitochondria and neuronal death/survival signaling pathways in cerebral ischemia. Neurochem Res 29:1943–1949
Reddy PH, Beal MF (2005) Are mitochondria critical in the pathogenesis of Alzheimer’s disease? Brain Res Rev 49:618–632
Toescu EC, Verkhratsky A (2004) Ca2+ and mitochondria as substrates for deficits in synaptic plasticity in normal brain ageing. J Cell Mol Med 8:181–190
Liu D, Lu C, Wan R, Auyeung W, Mattson MP (2002) Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome c release. J Cereb Blood Flow Metab 22:431–443
Hashimoto M, Rockenstein E, Crews L, Masliah E (2003) Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromolecular Med 4:21–36
Mattson MP, Partin J, Begley JG. 1998b. Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites. Brain Res 807:167–176
Ivins KJ, Bui ET, Cotman CW (1998) Beta-amyloid induces local neurite degeneration in cultured hippocampal neurons: evidence for neuritic apoptosis. Neurobiol Dis 5:365–378
Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP (1997a) A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J Neurochem 68:255–264
Mark RJ, Pang Z, Geddes JW, Uchida K, Mattson MP. 1997b. Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J Neurosci 17:1046–1054
Blanc EM, Kelly JF, Mark RJ, Waeg G, Mattson MP (1997) 4-Hydroxynonenal, an aldehydic product of lipid peroxidation, impairs signal transduction associated with muscarinic acetylcholine and metabotropic glutamate receptors: possible action on G alpha(q/11). J Neurochem 69:570–580
Keller JN, Pang Z, Geddes JW, Begley JG, Germeyer A, Waeg G, Mattson MP (1997) Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid beta-peptide: role of the lipid peroxidation product 4-hydroxynonenal. J Neurochem 69:273–284
Mattson MP, Keller JN, Begley JG (1998a) Evidence for synaptic apoptosis. Exp Neurol 153:35–48
Jonas EA, Hickman JA, Hardwick JM, Kaczmarek LK (2005b) Exposure to hypoxia rapidly induces mitochondrial channel activity within a living synapse. J Biol Chem 280:4491–4497
Albensi BC, Sullivan PG, Thompson MB, Scheff SW, Mattson MP (2000) Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity. Exp Neurol 162:385–389
Einat H, Yuan P, Manji HK (2005) Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders. Behav Brain Res 165:172–180
Stork C, Renshaw PF (2005) Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry 10:900–919
Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S (2004) Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 61:300–308
Kung L, Roberts RC (1999) Mitochondrial pathology in human schizophrenic striatum: a postmortem ultrastructural study. Synapse 31:67–75
Karry R, Klein E, Ben Shachar D (2004) Mitochondrial complex I subunits expression is altered in schizophrenia: a postmortem study. Biol Psychiatry 55:676–684
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This work was supported by the National Institute on Aging Intramural Research Program of the National Institutes of Health.
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Special issue dedicated to John P. Blass.
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Mattson, M.P. Mitochondrial Regulation of Neuronal Plasticity. Neurochem Res 32, 707–715 (2007). https://doi.org/10.1007/s11064-006-9170-3
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DOI: https://doi.org/10.1007/s11064-006-9170-3