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1.
Front Neural Circuits ; 7: 189, 2013.
Article in English | MEDLINE | ID: mdl-24324408

ABSTRACT

In many rodent brain regions, alcohol increases vesicular release of GABA, resulting in an increase in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and the magnitude of tonic GABAA receptor (GABAAR) currents. A neglected issue in translating the rodent literature to humans is the possibility that phylogenetic differences alter the actions of alcohol. To address this issue we made voltage-clamp recordings from granule cells (GCs) in cerebellar slices from the non-human primate (NHP), Macaca fascicularis. We found that similar to Sprague Dawley rats (SDRs), NHP GCs exhibit a tonic conductance generated by α6δ subunit containing GABAARs, as evidenced by its blockade by the broad spectrum GABAAR antagonist, GABAzine (10 µM), inhibition by α6 selective antagonist, furosemide (100 µM), and enhancement by THDOC (10-20 nM) and THIP (500 nM). In contrast to SDR GCs, in most NHP GCs (~60%), application of EtOH (25-105 mM) did not increase sIPSC frequency or the tonic GABAAR current. In a minority of cells (~40%), EtOH did increase sIPSC frequency and the tonic current. The relative lack of response to EtOH was associated with reduced expression of neuronal nitric oxide synthase (nNOS), which we recently reported mediates EtOH-induced enhancement of vesicular GABA release in rats. The EtOH-induced increase in tonic GABAAR current was significantly smaller in NHPs than in SDRs, presumably due to less GABA release, because there were no obvious differences in the density of GABAARs or GABA transporters between SDR and NHP GCs. Thus, EtOH does not directly modulate α6δ subunit GABAARs in NHPs. Instead, EtOH enhanced GABAergic transmission is mediated by enhanced GABA release. Further, SDR GC responses to alcohol are only representative of a subpopulation of NHP GCs. This suggests that the impact of EtOH on NHP cerebellar physiology will be reduced compared to SDRs, and will likely have different computational and behavioral consequences.


Subject(s)
Cerebellum/metabolism , Ethanol/pharmacology , Neural Conduction/physiology , Neurons/metabolism , Receptors, GABA-A/metabolism , Animals , Cerebellum/cytology , Cerebellum/drug effects , GABA-A Receptor Antagonists/pharmacology , Inhibitory Postsynaptic Potentials/drug effects , Inhibitory Postsynaptic Potentials/physiology , Macaca fascicularis , Neural Conduction/drug effects , Neurons/cytology , Neurons/drug effects , Nitric Oxide Synthase Type I/metabolism , Pyridazines/pharmacology , gamma-Aminobutyric Acid/metabolism
2.
Nature ; 461(7262): 367-72, 2009 Sep 17.
Article in English | MEDLINE | ID: mdl-19710649

ABSTRACT

Mitochondria are found in all eukaryotic cells and contain their own genome (mitochondrial DNA or mtDNA). Unlike the nuclear genome, which is derived from both the egg and sperm at fertilization, the mtDNA in the embryo is derived almost exclusively from the egg; that is, it is of maternal origin. Mutations in mtDNA contribute to a diverse range of currently incurable human diseases and disorders. To establish preclinical models for new therapeutic approaches, we demonstrate here that the mitochondrial genome can be efficiently replaced in mature non-human primate oocytes (Macaca mulatta) by spindle-chromosomal complex transfer from one egg to an enucleated, mitochondrial-replete egg. The reconstructed oocytes with the mitochondrial replacement were capable of supporting normal fertilization, embryo development and produced healthy offspring. Genetic analysis confirmed that nuclear DNA in the three infants born so far originated from the spindle donors whereas mtDNA came from the cytoplast donors. No contribution of spindle donor mtDNA was detected in offspring. Spindle replacement is shown here as an efficient protocol replacing the full complement of mitochondria in newly generated embryonic stem cell lines. This approach may offer a reproductive option to prevent mtDNA disease transmission in affected families.


Subject(s)
DNA, Mitochondrial/genetics , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Genes, Mitochondrial/genetics , Genome, Mitochondrial/genetics , Macaca mulatta/genetics , Reproductive Techniques, Assisted , Animals , Cell Nucleus/genetics , DNA, Mitochondrial/analysis , Embryo Transfer , Embryonic Stem Cells/transplantation , Female , Fertilization in Vitro , Macaca mulatta/embryology , Male , Meiosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/prevention & control , Mutation , Oocytes/cytology , Oocytes/metabolism , Pregnancy
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