Abstract
Individual synapses vary significantly in their neurotransmitter release properties, which underlie complex information processing in neural circuits. Presynaptic Ca2+ homeostasis plays a critical role in specifying neurotransmitter release properties, but the mechanisms regulating synapse-specific Ca2+ homeostasis in the mammalian brain are still poorly understood. Using electrophysiology and genetically encoded Ca2+ sensors targeted to the mitochondrial matrix or to presynaptic boutons of cortical pyramidal neurons, we demonstrate that the presence or absence of mitochondria at presynaptic boutons dictates neurotransmitter release properties through Mitochondrial Calcium Uniporter (MCU)-dependent Ca2+ clearance. We demonstrate that the serine/threonine kinase LKB1 regulates MCU expression, mitochondria-dependent Ca2+ clearance, and thereby, presynaptic release properties. Re-establishment of MCU-dependent mitochondrial Ca2+ uptake at glutamatergic synapses rescues the altered neurotransmitter release properties characterizing LKB1-null cortical axons. Our results provide novel insights into the cellular and molecular mechanisms whereby mitochondria control neurotransmitter release properties in a bouton-specific way through presynaptic Ca2+ clearance.
Highlights
Neurotransmitter release properties vary greatly between presynaptic terminals of different neurons, and between presynaptic release sites of the same neuron
Our results demonstrate that the presence of a presynaptic mitochondria plays a key role in calcium homeostasis and, thereby, regulates the properties of PLOS Biology | DOI:10.1371/journal.pbio
Our results suggest that mitochondrial capture at individual presynaptic boutons along cortical axon plays a synapse-specific role in regulating neurotransmission through the ability to regulate presynaptic calcium homeostasis
Summary
Neurotransmitter release properties vary greatly between presynaptic terminals of different neurons, and between presynaptic release sites of the same neuron. Rapid calcium (Ca2+) influx through voltage-gated Ca2+ channels (VGCC) triggers exocytosis of neurotransmitter vesicles on a sub-millisecond timescale. Several studies revealed that action potential (AP)-evoked presynaptic Ca2+ signals can vary drastically between different boutons along the same axons [5,6,7,8]. In cortical pyramidal neurons, individual presynaptic release sites distributed along a single axon have different patterns of Ca2+ dynamics and neurotransmitter release probability depending on the postsynaptic target cells [5, 9,10,11,12,13]. The cellular and molecular pathways regulating Ca2+ dynamics in a synapse-specific way are poorly understood
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