Frequency facilitation at mossy fiber-CA3 synapses of freely behaving rats contributes to the induction of persistent LTD via an adenosine-A1 receptor-regulated mechanism

Cereb Cortex. 2010 May;20(5):1121-30. doi: 10.1093/cercor/bhp184. Epub 2009 Nov 10.


Frequency facilitation (FF), comprising a rapid and multiple-fold increase in the magnitude of evoked field potentials, is elicited by low-frequency stimulation (LFS) at mossy fiber-CA3 synapses. Here, we show that in freely behaving rats, FF reliably occurs in response to 1 and 2Hz but not in response to 0.25-, 0.3-, or 0.5-Hz LFS. Strikingly, prolonged (approximately 600 s) FF was tightly correlated to the induction of long-term depression (LTD) in freely moving animals. Although LFS at 2 Hz elicited unstable FF and unstable LTD, application of LFS at 1 Hz elicited pronounced FF, as well as robust LTD that persisted for over 24 h. This correlation of prolonged FF with LTD was absent at stimulation frequencies that did not induce FF. The adenosine-A1 receptor appears to participate in these effects: Application of adenosine-A1, but not adenosine-A3, receptor antagonists enhanced mossy fiber synaptic transmission and occluded FF. Furthermore, adenosine-A1 receptor antagonism resulted in more stable FF at 1 or 2 Hz and elicited more potent LTD. These data support the fact that FF contributes to the enablement of long-term information storage at mossy fiber-CA3 synapses and that the adenosine-A1 receptor may regulate the thresholds for this process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A1 Receptor Antagonists
  • Analysis of Variance
  • Animals
  • Biophysics
  • CA3 Region, Hippocampal / physiology*
  • Cyclopropanes / pharmacology
  • Dihydropyridines / pharmacology
  • Electric Stimulation / methods
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Long-Term Synaptic Depression / physiology*
  • Male
  • Mossy Fibers, Hippocampal / physiology*
  • Rats
  • Rats, Wistar
  • Receptor, Adenosine A1 / physiology*
  • Statistics as Topic
  • Time Factors
  • Valine / analogs & derivatives
  • Valine / pharmacology
  • Wakefulness / physiology*
  • Xanthines / pharmacology
  • Xylenes / pharmacology


  • Adenosine A1 Receptor Antagonists
  • Cyclopropanes
  • Dihydropyridines
  • Excitatory Amino Acid Antagonists
  • MRS 1191
  • Receptor, Adenosine A1
  • Xanthines
  • Xylenes
  • 2-(2,3-dicarboxycyclopropyl)glycine
  • (1-phenylethyl)xylene
  • 2-amino-5-phosphopentanoic acid
  • 1,3-dipropyl-8-cyclopentylxanthine
  • Valine
  • Glycine