PMID- 25241069 OWN - NLM STAT- MEDLINE DCOM- 20150812 LR - 20161125 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 280 DP - 2014 Nov 7 TI - In vivo mitochondrial inhibition alters corticostriatal synaptic function and the modulatory effects of neurotrophins. PG - 156-70 LID - S0306-4522(14)00760-X [pii] LID - 10.1016/j.neuroscience.2014.09.018 [doi] AB - 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). CI - Copyright (c) 2014 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Mendoza, E AU - Mendoza E AD - Unidad de Biomedicina, FES-I, Universidad Nacional Autonoma de Mexico, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico. FAU - Miranda-Barrientos, J A AU - Miranda-Barrientos JA AD - Unidad de Biomedicina, FES-I, Universidad Nacional Autonoma de Mexico, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico. FAU - Vazquez-Roque, R A AU - Vazquez-Roque RA AD - Instituto de Fisiologia, Universidad Autonoma de Puebla, 14 sur 6301, San Manuel, C.P. 72570 Puebla, Mexico. FAU - Morales-Herrera, E AU - Morales-Herrera E AD - Instituto de Fisiologia, Universidad Autonoma de Puebla, 14 sur 6301, San Manuel, C.P. 72570 Puebla, Mexico. FAU - Ruelas, A AU - Ruelas A AD - Unidad de Biomedicina, FES-I, Universidad Nacional Autonoma de Mexico, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico. FAU - De la Rosa, G AU - De la Rosa G AD - Unidad de Biomedicina, FES-I, Universidad Nacional Autonoma de Mexico, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico. FAU - Flores, G AU - Flores G AD - Instituto de Fisiologia, Universidad Autonoma de Puebla, 14 sur 6301, San Manuel, C.P. 72570 Puebla, Mexico. FAU - Hernandez-Echeagaray, E AU - Hernandez-Echeagaray E AD - Unidad de Biomedicina, FES-I, Universidad Nacional Autonoma de Mexico, Av. de Los Barrios # 1, Los Reyes Iztacala, C.P. 54090 Tlalnepantla, Mexico. Electronic address: elihernandez@campus.iztacala.unam.mx. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140918 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Nerve Growth Factors) RN - 0 (Neurotrophin 3) RN - 0 (Nitro Compounds) RN - 0 (Propionates) RN - 0 (Receptors, Nerve Growth Factor) RN - 145172-44-7 (neurotrophin 5) RN - 3KX376GY7L (Glutamic Acid) RN - P658DCA9XD (neurotrophin 4) RN - QY4L0FOX0D (3-nitropropionic acid) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cerebral Cortex/drug effects/pathology/*physiology MH - Corpus Striatum/drug effects/pathology/*physiology MH - Glutamic Acid/metabolism MH - Male MH - Mice, Inbred C57BL MH - Mitochondria/drug effects/*physiology MH - Mitochondrial Diseases MH - Nerve Growth Factors/*metabolism MH - Neural Pathways/drug effects/pathology/physiology MH - Neurotrophin 3/metabolism MH - Nitro Compounds/toxicity MH - Propionates/toxicity MH - Random Allocation MH - Receptors, Nerve Growth Factor/metabolism MH - Synapses/drug effects/pathology/*physiology MH - Synaptic Transmission/*physiology MH - Tissue Culture Techniques OTO - NOTNLM OT - 3-NP OT - dendrites OT - mitochondria OT - neurodegeneration OT - neurotrophins OT - striatum EDAT- 2014/09/23 06:00 MHDA- 2015/08/13 06:00 CRDT- 2014/09/22 06:00 PHST- 2014/08/24 00:00 [received] PHST- 2014/09/09 00:00 [accepted] PHST- 2014/09/22 06:00 [entrez] PHST- 2014/09/23 06:00 [pubmed] PHST- 2015/08/13 06:00 [medline] AID - S0306-4522(14)00760-X [pii] AID - 10.1016/j.neuroscience.2014.09.018 [doi] PST - ppublish SO - Neuroscience. 2014 Nov 7;280:156-70. doi: 10.1016/j.neuroscience.2014.09.018. Epub 2014 Sep 18.