title: In vivo mitochondrial inhibition alters corticostriatal synaptic function and the modulatory effects of neurotrophins.
abstract: Experimental evidence has revealed the role of mitochondria in various aspects of neuronal physiology. Mitochondrial failure results in alterations that underlie the pathogeneses of many neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease (HD) and amyotrophic lateral sclerosis. The mitochondrial toxin 3-nitropropionic acid (3-NP) has been used to model failure; for example, systemic administration of 3-NP imitates the striatal degeneration that is exhibited in the postmortem tissue of patients afflicted with HD. We have demonstrated that low, sub-chronic doses of 3-NP are sufficient to initiate the damage to striatal neurons that is associated with changes in neurotrophin expression levels. However, the mechanisms underlying the alterations in neuronal activity and neurotransmission due to 3-NP-induced mitochondrial dysfunction remain to be elucidated. In this paper, we focus on how corticostriatal transmission and its modulation by neurotrophins are altered in vivo after 5 days of mitochondrial inhibition with 3-NP. Recordings of population spikes and a paired pulse (PP) stimulation protocol were used to document changes in corticostriatal synapses in 3-NP-treated brain slices. The corticostriatal synapses were modulated by neurotrophins but displayed differential amplitude increases in the presence of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4/5 (NT-4/5) under control conditions. Neurotrophin-mediated synaptic modulation was decreased in slices from 3-NP-treated mice. The protein and mRNA levels of neurotrophins and their receptors were also modified in the 3-NP-treated tissue. Neuronal structural evaluation demonstrated that synaptic length and density were reduced in the 3-NP-treated mice, which partially explained the changes in the amplitudes of the synaptic field responses. Our results demonstrate that corticostriatal synapses are differentially modulated by neurotrophins and that this modulation is altered by mitochondrial failure. Mitochondrial dysfunction also affects neurotransmitter release in corticostriatal synapses, neurotrophin availability, dendritic arborization and the lengths of the striatal medium spiny neurons (MSNs).
authors.affiliation: Unidad de Biomedicina, FES-I, Universidad Nacional Autónoma de México, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico.
authors.forename: E
authors.initials: E
authors.lastname: Mendoza
authors.affiliation: Unidad de Biomedicina, FES-I, Universidad Nacional Autónoma de México, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico.
authors.forename: J A
authors.initials: JA
authors.lastname: Miranda-Barrientos
authors.affiliation: Instituto de Fisiología, Universidad Autónoma de Puebla, 14 sur 6301, San Manuel, C.P. 72570 Puebla, Mexico.
authors.forename: R A
authors.initials: RA
authors.lastname: Vázquez-Roque
authors.affiliation: Instituto de Fisiología, Universidad Autónoma de Puebla, 14 sur 6301, San Manuel, C.P. 72570 Puebla, Mexico.
authors.forename: E
authors.initials: E
authors.lastname: Morales-Herrera
authors.affiliation: Unidad de Biomedicina, FES-I, Universidad Nacional Autónoma de México, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico.
authors.forename: A
authors.initials: A
authors.lastname: Ruelas
authors.affiliation: Unidad de Biomedicina, FES-I, Universidad Nacional Autónoma de México, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico.
authors.forename: G
authors.initials: G
authors.lastname: De la Rosa
authors.affiliation: Instituto de Fisiología, Universidad Autónoma de Puebla, 14 sur 6301, San Manuel, C.P. 72570 Puebla, Mexico.
authors.forename: G
authors.initials: G
authors.lastname: Flores
authors.affiliation: Unidad de Biomedicina, FES-I, Universidad Nacional Autónoma de México, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico. Electronic address: elihernandez@campus.iztacala.unam.mx.
authors.forename: E
authors.initials: E
authors.lastname: Hernández-Echeagaray
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D028361:Mitochondrial Diseases; D009414:Nerve Growth Factors / Q000378:metabolism*; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020933:Neurotrophin 3 / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity; D011422:Propionates / Q000633:toxicity; D011897:Random Allocation; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D009574:Nitro Compounds; D011422:Propionates; D017475:Receptors, Nerve Growth Factor; C071951:neurotrophin 5; D018698:Glutamic Acid; C073922:neurotrophin 4; C015392:3-nitropropionic acid
keywords: 3-NP; dendrites; mitochondria; neurodegeneration; neurotrophins; striatum