Mitochondrial Ca(2+) uniporter haploinsufficiency enhances long-term potentiation at hippocampal mossy fibre synapses

Long-term changes in synaptic strength form the basis of learning and memory. These changes rely upon energy-demanding mechanisms, which are regulated by local Ca(2+) signalling. Mitochondria are optimised for providing energy and buffering Ca(2+). However, our understanding of the role of mitochondria in regulating synaptic plasticity is incomplete. Here, we have used optical and electrophysiological techniques in cultured hippocampal neurons and ex vivo hippocampal slices from mice with haploinsufficiency of the mitochondrial Ca(2+) uniporter (MCU(+/−)) to address whether reducing mitochondrial Ca(2+) uptake alters synaptic transmission and plasticity. We found that cultured MCU(+/−) hippocampal neurons have impaired Ca(2+) clearance, and consequently enhanced synaptic vesicle fusion at presynapses occupied by mitochondria. Furthermore, long-term potentiation (LTP) at mossy fibre (MF) synapses, a process which is dependent on presynaptic Ca(2+) accumulation, is enhanced in MCU(+/−) slices. Our results reveal a previously unrecognised role for mitochondria in regulating presynaptic plasticity of a major excitatory pathway involved in learning and memory.