On the origin of ultraslow spontaneous Na+ fluctuations in neurons of the neonatal forebrain

J Neurophysiol. 2021 Feb 1;125(2):408-425. doi: 10.1152/jn.00373.2020. Epub 2020 Nov 25.


Spontaneous neuronal and astrocytic activity in the neonate forebrain is believed to drive the maturation of individual cells and their integration into complex brain-region-specific networks. The previously reported forms include bursts of electrical activity and oscillations in intracellular Ca2+ concentration. Here, we use ratiometric Na+ imaging to demonstrate spontaneous fluctuations in the intracellular Na+ concentration of CA1 pyramidal neurons and astrocytes in tissue slices obtained from the hippocampus of mice at postnatal days 2-4 (P2-4). These occur at very low frequency (∼2/h), can last minutes with amplitudes up to several millimolar, and mostly disappear after the first postnatal week. To further investigate their mechanisms, we model a network consisting of pyramidal neurons and interneurons. Experimentally observed Na+ fluctuations are mimicked when GABAergic inhibition in the simulated network is made depolarizing. Both our experiments and computational model show that blocking voltage-gated Na+ channels or GABAergic signaling significantly diminish the neuronal Na+ fluctuations. On the other hand, blocking a variety of other ion channels, receptors, or transporters including glutamatergic pathways does not have significant effects. Our model also shows that the amplitude and duration of Na+ fluctuations decrease as we increase the strength of glial K+ uptake. Furthermore, neurons with smaller somatic volumes exhibit fluctuations with higher frequency and amplitude. As opposed to this, larger extracellular to intracellular volume ratio observed in neonatal brain exerts a dampening effect. Finally, our model predicts that these periods of spontaneous Na+ influx leave neonatal neuronal networks more vulnerable to seizure-like states when compared with mature brain.NEW & NOTEWORTHY Spontaneous activity in the neonate forebrain plays a key role in cell maturation and brain development. We report spontaneous, ultraslow, asynchronous fluctuations in the intracellular Na+ concentration of neurons and astrocytes. We show that this activity is not correlated with the previously reported synchronous neuronal population bursting or Ca2+ oscillations, both of which occur at much faster timescales. Furthermore, extracellular K+ concentration remains nearly constant. The spontaneous Na+ fluctuations disappear after the first postnatal week.

Keywords: depolarizing GABA; hyperactivity; ion dynamics; neonatal brain; spontaneous Na+ fluctuations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials*
  • Animals
  • Female
  • GABA Antagonists / pharmacology
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / physiology
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Interneurons / physiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Neurological
  • Prosencephalon / cytology
  • Prosencephalon / metabolism
  • Prosencephalon / physiology*
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / physiology
  • Sodium / metabolism*
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / metabolism*


  • GABA Antagonists
  • Sodium Channel Blockers
  • Sodium Channels
  • Sodium