Activity-dependent neuron-glial signaling by ATP and leukemia-inhibitory factor promotes hippocampal glial cell development

Neuron Glia Biol. 2008 Feb;4(1):43-55. doi: 10.1017/S1740925X09000076.


Activity-dependent signaling between neurons and astrocytes contributes to experience-dependent plasticity and development of the nervous system. However, mechanisms responsible for neuron-glial interactions and the releasable factors that underlie these processes are not well understood. The pro-inflammatory cytokine, leukemia-inhibitory factor (LIF), is transiently expressed postnatally by glial cells in the hippocampus and rapidly up-regulated by enhanced neural activity following seizures. To test the hypothesis that spontaneous neural activity regulates glial development in hippocampus via LIF signaling, we blocked spontaneous activity with the sodium channel blocker tetrodotoxin (TTX) in mixed hippocampal cell cultures in combination with blockers of LIF and purinergic signaling. TTX decreased the number of GFAP-expressing astrocytes in hippocampal cell culture. Furthermore, blocking purinergic signaling by P2Y receptors contributed to reduced numbers of astrocytes. Blocking activity or purinergic signaling in the presence of function-blocking antibodies to LIF did not further decrease the number of astrocytes. Moreover, hippocampal cell cultures prepared from LIF -/- mice had reduced numbers of astrocytes and activity-dependent neuron-glial signaling promoting differentiation of astrocytes was absent. The results show that endogenous LIF is required for normal development of hippocampal astrocytes, and this process is regulated by spontaneous neural impulse activity through the release of ATP.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Astrocytes / cytology
  • Astrocytes / metabolism*
  • Cell Communication / physiology
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Female
  • Hippocampus / cytology
  • Hippocampus / growth & development*
  • Hippocampus / metabolism*
  • Leukemia Inhibitory Factor / genetics*
  • Male
  • Mice
  • Mice, Knockout
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Neurons / metabolism
  • Purinergic P2 Receptor Antagonists
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2 / metabolism
  • Receptors, Purinergic P2Y1
  • Signal Transduction / physiology
  • Sodium Channel Blockers / pharmacology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Tetrodotoxin / pharmacology
  • Up-Regulation / physiology


  • Leukemia Inhibitory Factor
  • Lif protein, mouse
  • P2ry1 protein, mouse
  • Purinergic P2 Receptor Antagonists
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y1
  • Sodium Channel Blockers
  • Tetrodotoxin
  • Adenosine Triphosphate