Presynaptic mitochondria calcium uniporter promotes auditory temporal processing during sustained high-rate activity

Mitochondrial calcium uniporter (MCU) uptakes calcium into mitochondria to maintain intracellular calcium homeostasis, malfunction of which has been implicated in altered neuronal signaling and disease. Its role in synaptic transmission remains understudied, especially in intact neural circuits. We investigated MCU function at the auditory nerve endbulb of Held synapse and postsynaptic bushy neurons in the cochlear nucleus, using age-matched control and MCU knockout (KO) mice of either sex. Whole-cell voltage-and current-clamp recordings were acquired from acute brain slices to examine synaptic transmission and postsynaptic responses. We found that basal synaptic properties at the endbulb of Held were unchanged in MCU KO mice, whereas synaptic transmission during sustained high-rate activity was significantly altered with a shift toward increased asynchronous release. Similarly, MCU deficiency did not change the intrinsic membrane properties of postsynaptic bushy neurons, but significantly reduced the temporal precision of auditory nerve evoked spikes trains at high rates. These results demonstrate that MCU is largely dispensable under low-rate activity, presumably because its activation requires relatively high calcium concentrations. In contrast, during sustained high-rate activity, MCU becomes an important regulator of synaptic function by reducing asynchronous neurotransmitter release under elevated intracellular calcium. Particularly in the auditory system, where neurons routinely fire at high rates, MCU promotes temporal processing and thereby plays a key role in supporting auditory function. It suggests that impaired MCU function under pathological conditions may be an important mechanism underlying central auditory processing deficits, and consequently contributes to hearing loss.

MCU uptakes calcium into mitochondria to regulate intracellular calcium, yet its contribution to synaptic transmission and neural processing remain understudied. Using a MCU KO mouse model, we investigated the role of MCU in synaptic transmission and postsynaptic responses at the endbulb of Held synapses and postsynaptic bushy neurons in the cochlear nucleus. The results showed that MCU plays little role in basal synaptic transmission, but significantly reduces asynchronous vesicle release during sustained high-rate activity, consequently improving temporal precision of the signal processing. These findings define the roles of MCU under different activity levels at the intact endulb/bushy connection, and suggest that impaired MCU function may be a key mechanism underlying central auditory processing deficits, and consequently contributes to hearing loss.