Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations

J Cereb Blood Flow Metab. 2020 Dec;40(12):2401-2415. doi: 10.1177/0271678X19892657. Epub 2019 Dec 16.


Disturbances of cognitive functions occur rapidly during acute metabolic stress. However, the underlying mechanisms are not fully understood. Cortical gamma oscillations (30-100 Hz) emerging from precise synaptic transmission between excitatory principal neurons and inhibitory interneurons, such as fast-spiking GABAergic basket cells, are associated with higher brain functions, like sensory perception, selective attention and memory formation. We investigated the alterations of cholinergic gamma oscillations at the level of neuronal ensembles in the CA3 region of rat hippocampal slice cultures. We combined electrophysiology, calcium imaging (CamKII.GCaMP6f) and mild metabolic stress that was induced by rotenone, a lipophilic and highly selective inhibitor of complex I in the respiratory chain of mitochondria. The detected pyramidal cell ensembles showing repetitive patterns of activity were highly sensitive to mild metabolic stress. Whereas such synchronised multicellular activity diminished, the overall activity of individual pyramidal cells was unaffected. Additionally, mild metabolic stress had no effect on the rate of action potential generation in fast-spiking neural units. However, the partial disinhibition of slow-spiking neural units suggests that disturbances of ensemble formation likely result from alterations in synaptic inhibition. Our study bridges disturbances on the (multi-)cellular and network level to putative cognitive impairment on the system level.

Keywords: Brain slice; cognition; electrophysiology; energy metabolism; widefield microscopy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Cognitive Dysfunction / metabolism*
  • Cognitive Dysfunction / physiopathology
  • Electrophysiology / methods
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Gamma Rhythm / drug effects
  • Gamma Rhythm / physiology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Hippocampus / physiopathology
  • Interneurons / classification
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / physiology
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / physiology
  • Rats
  • Rats, Wistar
  • Rotenone / administration & dosage
  • Rotenone / pharmacology
  • Stress, Physiological / drug effects*
  • Stress, Physiological / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Uncoupling Agents / administration & dosage
  • Uncoupling Agents / pharmacology


  • Uncoupling Agents
  • Rotenone