Mitochondrial calcium uptake capacity modulates neocortical excitability

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Local calcium (Ca2+) dynamics are crucial for central nervous system (CNS) metabolism and communication.
• Mitochondria facilitate Ca2+ uptake via the mitochondrial calcium uniporter (mCU), influenced by cytoplasmic microdomains.
• The in vivo significance of mCU activity in brain signaling and metabolism remains largely unexplored.

Purpose of the Study:

• To investigate the in vivo impact of mitochondrial calcium uniporter (mCU) activity on cortical neuronal activity and hemodynamic responses.
• To determine if modulating mCU activity influences Ca2+-dependent mitochondrial roles in brain function.
• To test the hypothesis that mCU inhibition or enhancement would attenuate or augment cortical activity, respectively.

Main Methods:

• Evaluated spontaneous and activity-induced Ca2+ distributions in vivo using extracellular electrophysiology and dynamic mapping of blood oxygen level dependence and cerebral blood flow.
• Pharmacologically inhibited mCU activity using Ru360 and enhanced it using Kaempferol.
• Analyzed the integrated impact of mCU modulation on multimodal measures of cortical activity.

Main Results:

• Inhibition of mCU activity with Ru360 significantly reduced all stimulus-evoked cortical responses.
• Enhancement of mCU activity with Kaempferol significantly augmented all stimulus-evoked cortical responses.
• Results demonstrated a clear Ca2+ uptake-dependent relationship between mCU activity and neocortical function.

Conclusions:

• Mitochondrial calcium uptake via the mCU plays an integral role in regulating in vivo neocortical activity.
• Modulation of mCU activity provides a potential mechanism for controlling neuronal excitability and associated hemodynamic changes.
• These findings highlight the importance of mitochondrial Ca2+ handling in brain signaling and metabolism.