Projects per year
Abstract
KEY POINTS: 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.
ABSTRACT: 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.
Original language | English |
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Pages (from-to) | 2147-2160 |
Number of pages | 14 |
Journal | The Journal of Physiology |
Volume | 595 |
Issue number | 6 |
Early online date | 12 Jan 2017 |
DOIs | |
Publication status | Published - 15 Mar 2017 |
Keywords / Materials (for Non-textual outputs)
- Journal Article
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Dive into the research topics of 'Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses'. Together they form a unique fingerprint.Projects
- 4 Finished
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Identifying how membrane proteins required for saltatory conduction are trafficked and stabilised in PNS axonal domains
Brophy, P. (Principal Investigator)
1/10/15 → 30/09/21
Project: Research
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Cause and Consequences of Mitochondrial Injury in Progressive Multiple Sclerosis
Mahad, D. (Principal Investigator)
1/08/14 → 31/12/15
Project: Research
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Imaging the assembly, disruption and restoration of nodes of Ranvier in myelinated nerves
Brophy, P. (Principal Investigator)
1/08/14 → 31/12/17
Project: Research
Profiles
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Don Mahad
- Deanery of Clinical Sciences - Senior Clinical Lecturer
- Centre for Clinical Brain Sciences
- Euan MacDonald Centre for Motor Neuron Disease Research
- Anne Rowling Regenerative Neurology Clinic
- Edinburgh Neuroscience
Person: Academic: Research Active