title: Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.
abstract: Neurodegenerative disorders can exhibit dysfunctional mitochondrial respiratory chain complex IV activity. Conditional deletion of cytochrome c oxidase, the terminal enzyme in the respiratory electron transport chain of mitochondria, from hippocampal dentate granule cells in mice does not affect low-frequency dentate to CA3 glutamatergic synaptic transmission. High-frequency dentate to CA3 glutamatergic synaptic transmission and feedforward inhibition are significantly attenuated in cytochrome c oxidase-deficient mice. Intact presynaptic mitochondrial function is critical for the short-term dynamics of mossy fibre to CA3 synaptic function.
  
  
  
  Neurodegenerative disorders are characterized by peripheral and central symptoms including cognitive impairments which have been associated with reduced mitochondrial function, in particular mitochondrial respiratory chain complex IV or cytochrome c oxidase activity. In the present study we conditionally removed a key component of complex IV, protohaem IX farnesyltransferase encoded by the COX10 gene, in granule cells of the adult dentate gyrus. Utilizing whole-cell patch-clamp recordings from morphologically identified CA3 pyramidal cells from control and complex IV-deficient mice, we found that reduced mitochondrial function did not result in overt deficits in basal glutamatergic synaptic transmission at the mossy-fibre synapse because the amplitude, input-output relationship and 50 ms paired-pulse facilitation were unchanged following COX10 removal from dentate granule cells. However, trains of stimuli given at high frequency (> 20 Hz) resulted in dramatic reductions in short-term facilitation and, at the highest frequencies (> 50 Hz), also reduced paired-pulse facilitation, suggesting a requirement for adequate mitochondrial function to maintain glutamate release during physiologically relevant activity patterns. Interestingly, local inhibition was reduced, suggesting the effect observed was not restricted to synapses with CA3 pyramidal cells via large mossy-fibre boutons, but rather to all synapses formed by dentate granule cells. Therefore, presynaptic mitochondrial function is critical for the short-term dynamics of synapse function, which may contribute to the cognitive deficits observed in pathological mitochondrial dysfunction.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.|Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
authors.forename: Sam A
authors.initials: SA
authors.lastname: Booker
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Campbell
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Karolina S
authors.identifier: 0000-0002-4175-3581
authors.initials: KS
authors.lastname: Mysiak
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.|Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, 560065, India.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kind
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Mahad
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.|Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, 560065, India.
authors.forename: David J A
authors.identifier: 0000-0002-4957-6049
authors.initials: DJ
authors.lastname: Wyllie
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000502:physiology*; D018891:Dentate Gyrus / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008822:Mice, Transgenic; D019599:Mossy Fibers, Hippocampal / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D008565:Membrane Proteins; D019883:Alkyl and Aryl Transferases; C512252:COX10 protein, mouse