Inhibiting the Mitochondrial Calcium Uniporter during Development Impairs Memory in Adult Drosophila

Abstract

Summary The uptake of cytoplasmic calcium into mitochondria is critical for a variety of physiological processes, including calcium buffering, metabolism and cell survival. We demonstrate here that inhibiting the mitochondrial calcium uniporter in the Drosophila mushroom body neurons (MBn) – a brain region critical for olfactory memory formation – causes memory impairment without altering the capacity to learn. Inhibiting uniporter activity only during pupation impaired adult memory, whereas the same inhibition during adulthood was without effect. The behavioral impairment was associated with structural defects in MBn, including a decrease in synaptic vesicles and an increased length in the axons of the αβ MBn. Our results reveal an in vivo developmental role for the mitochondrial uniporter complex in establishing the necessary structural and functional neuronal substrates for normal memory formation in the adult organism.

Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models

“…Decreased mitochondrial Ca 2+ accumulation, triggered by overexpression of a dominant-negative isoform of MCU in mushroom body neurons, causes axon lengthening accompanied by decreased synaptic vesicle content [25]. A recent report focused on the role of mitochondrial Ca 2+ uptake in dopaminergic neurons.…”

Mechanical activation of TWIK-related potassium channel by nanoscopic movement and rapid second messenger signaling

“…Vibration motor was attached to the back of the chamber with the flies and flies were monitored using a web camera for stimulation-induced arousal (bottom). (c) Shock avoidance responses were measured by placing the PLD-KD flies at the choice-point of a T maze in which they could then choose between a chamber inducing noxious shock or a non-shock control 66 . Flies were subjected to increasing voltages of shock and an avoidance ratio was measured as previously described 66 .…”

“…(c) Shock avoidance responses were measured by placing the PLD-KD flies at the choice-point of a T maze in which they could then choose between a chamber inducing noxious shock or a non-shock control 66 . Flies were subjected to increasing voltages of shock and an avoidance ratio was measured as previously described 66 . Shock avoidance index (AI) was calculated as = (# ℎ − # ) # ⁄ .…”

Pharmacological modulation of mitochondrial calcium homeostasis

“…Similar to human patients carrying loss-of-function MICU1 mutations, viable MICU1 knockout mice revealed a strong phenotype, including atypical mitochondrial morphology, reduced muscle ATP levels and features of neuromuscular disorders such as ataxia (Logan et al 2014). Reminiscent of these features, silencing of MCU and MICU1 in Drosophila melanogaster during development in a brain region essential for memory resulted in impaired memory formation in adulthood without affecting the learning ability (Drago & Davis, 2016). In contrast to the lethality phenotype observed for the MICU1-null mice, constitutive loss of MICU2 in pure C57BL/6 background mice was recently found to be compatible with life and development, although leading to alterations in cardiovascular homeostasis associated with diastolic heart failure (Bick et al 2017).…”

“…). Reminiscent of these features, silencing of MCU and MICU1 in Drosophila melanogaster during development in a brain region essential for memory resulted in impaired memory formation in adulthood without affecting the learning ability (Drago & Davis, ). In contrast to the lethality phenotype observed for the MICU1 ‐null mice, constitutive loss of MICU2 in pure C57BL/6 background mice was recently found to be compatible with life and development, although leading to alterations in cardiovascular homeostasis associated with diastolic heart failure (Bick et al .…”