Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.

Sam A Booker,Peter C Kind,Graham R Campbell,Peter J Brophy,Don J Mahad,Karolina S Mysiak,David J A Wyllie

doi:10.1113/jp273581

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. 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.

Highlights

Neurodegenerative disorders are highly debilitating and progressive neurological diseases, typified by symptoms localized to the peripheral and central nervous system (CNS) (Simon & Johns, 1999)
In the current study we show that mitochondrial respiratory chain complex IV deficiency, through conditional loss of protohaem IX farnesyltransferase achieved by selective removal of the COX10 gene in dentate granule cell (DGC), does not affect basal synaptic transmission of the dentate gyrus (DG)–CA3 mossy-fibre bouton (MFB) synapse
These data indicate that intact mitochondrial function, and ATP generation, is a prerequisite for correct synaptic function, and compromised short-term plasticity and recruitment of inhibition associated with mitochondrial dysfunction may contribute to some of the cognitive phenotypes associated with neurodegenerative disorders

Summary

Introduction

Neurodegenerative disorders are highly debilitating and progressive neurological diseases, typified by symptoms localized to the peripheral and central nervous system (CNS) (Simon & Johns, 1999). The glutamatergic dentate granule cell (DGC) synapse onto CA3 pyramidal cells (CA3 PCs) in the hippocampus is one of the most widely studied of the central synapses This very large (3–5 μm) mossy-fibre bouton (MFB) synapse serves as the main transfer of synaptic information from the DG to the CA3, containing multiple mitochondria due to their large size and high energy requirement (Hamlyn, 1962). To address whether loss of COX10, and mitochondrial respiratory chain complex IV activity, leads to compromised synaptic transmission and short-term plasticity in the MF pathway we performed whole-cell electrophysiological recordings from identified CA3 PCs and DGCs in acute hippocampal slices from a mouse model, where an inducible COX10 deletion was performed preferentially from neurons using a Thy-1 promoter, preferentially expressed in the DG. Recordings of evoked synaptic currents showed that there is a requirement for intact mitochondrial function in the maintenance of short-term plasticity at MFBs, and the recruitment of feedforward inhibition, onto CA3 PCs

Ethical approval

Results

Discussion

20 Hz 50 Hz 100 Hz Stimulus frequency