Heterosynaptic long-term depression mediated by ATP released from astrocytes

Glia. 2013 Feb;61(2):178-91. doi: 10.1002/glia.22425. Epub 2012 Oct 8.

Abstract

Heterosynaptic long-term depression (hLTD) at untetanized synapses accompanying the induction of long-term potentiation (LTP) spatially sharpens the activity-induced synaptic potentiation; however, the underlying mechanism remains unclear. We found that hLTD in the hippocampal CA1 region is caused by stimulation-induced ATP release from astrocytes that suppresses transmitter release from untetanized synaptic terminals via activation of P2Y receptors. Selective stimulation of astrocytes expressing channelrhodopsin-2, a light-gated cation channel permeable to Ca(2+) , resulted in LTD of synapses on neighboring neurons. This synaptic modification required Ca(2+) elevation in astrocytes and activation of P2Y receptors, but not N-methyl-D-aspartate receptors. Furthermore, blocking P2Y receptors or buffering astrocyte intracellular Ca(2+) at a low level prevented hLTD without affecting LTP induced by SC stimulation. Thus, astrocyte activation is both necessary and sufficient for mediating hLTD accompanying LTP induction, strongly supporting the notion that astrocytes actively participate in activity-dependent synaptic plasticity of neural circuits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / pharmacology
  • Adenosine Diphosphate / analogs & derivatives
  • Adenosine Diphosphate / pharmacology
  • Adenosine Triphosphate / metabolism*
  • Adenosine Triphosphate / pharmacology*
  • Animals
  • Antigens / metabolism
  • Astrocytes / chemistry*
  • Astrocytes / metabolism
  • Biophysics
  • Calcium / metabolism
  • Calcium Signaling / physiology
  • Cells, Cultured
  • Channelrhodopsins
  • Electric Stimulation
  • Embryo, Mammalian
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Genetic Vectors / physiology
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Green Fluorescent Proteins / genetics
  • Hippocampus / cytology
  • In Vitro Techniques
  • Long-Term Synaptic Depression / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / physiology
  • Optical Phenomena
  • Patch-Clamp Techniques
  • Proteoglycans / metabolism
  • Purinergic P1 Receptor Antagonists / pharmacology
  • Purinergic P2Y Receptor Antagonists / pharmacology
  • Rats
  • Serine / pharmacology
  • Theophylline / analogs & derivatives
  • Theophylline / pharmacology
  • Time Factors
  • Transfection

Substances

  • Antigens
  • Channelrhodopsins
  • Glial Fibrillary Acidic Protein
  • N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate
  • Proteoglycans
  • Purinergic P1 Receptor Antagonists
  • Purinergic P2Y Receptor Antagonists
  • chondroitin sulfate proteoglycan 4
  • Green Fluorescent Proteins
  • 8-cyclopentyl-1,3-dimethylxanthine
  • Serine
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Theophylline
  • Adenosine
  • Calcium