Activation of α7-containing nicotinic receptors on astrocytes triggers AMPA receptor recruitment to glutamatergic synapses

J Neurochem. 2013 Dec;127(5):632-43. doi: 10.1111/jnc.12436. Epub 2013 Sep 30.

Abstract

Astrocytes, an abundant form of glia, are known to promote and modulate synaptic signaling between neurons. They also express α7-containing nicotinic acetylcholine receptors (α7-nAChRs), but the functional relevance of these receptors is unknown. We show here that stimulation of α7-nAChRs on astrocytes releases components that induce hippocampal neurons to acquire more α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors post-synaptically at glutamatergic synapses. The increase is specific in that no change is seen in synaptic NMDA receptor clusters or other markers for glutamatergic synapses, or in markers for GABAergic synapses. Moreover, the increases in AMPA receptors on the neuron surface are accompanied by increases in the frequency of spontaneous miniature synaptic currents mediated by the receptors and increases in the ratio of evoked synaptic currents mediated by AMPA versus NMDA receptors. This suggests that stimulating α7-nAChRs on astrocytes can convert 'silent' glutamatergic synapses to functional status. Astrocyte-derived thrombospondin is necessary but not sufficient for the effect, while tumor necrosis factor-α is sufficient but not necessary. The results identify astrocyte α7-nAChRs as a novel pathway through which nicotinic cholinergic signaling can promote the development of glutamatergic networks, recruiting AMPA receptors to post-synaptic sites and rendering the synapses more functional. We find that activation of nicotinic receptors on astrocytes releases a component that specifically recruits AMPA receptors to glutamatergic synapses. The recruitment appears to occur preferentially at what may be 'silent synapses', that is, synapses that have all the components required for glutamatergic transmission (including NMDA receptors) but lack sufficient AMPA receptors to generate a response. The results are unexpected and open up new possibilities for mechanisms underlying network formation and synaptic plasticity.

Keywords: AMPA receptors; astrocytes; cholinergic; glutamatergic; nicotinic; synapse formation.

Publication types

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

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Female
  • Glutamic Acid / metabolism
  • Hippocampus / cytology*
  • Male
  • Organ Culture Techniques
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism*
  • Signal Transduction / physiology
  • Synapses / metabolism
  • Synaptic Transmission / physiology
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*

Substances

  • Chrna7 protein, rat
  • Receptors, AMPA
  • alpha7 Nicotinic Acetylcholine Receptor
  • Glutamic Acid