Allosteric Modulation of Ligand-Gated Ion Channels Synergistically Induces Long-Term Potentiation in the Hippocampus and Enhances Cognition

Strategic Insights -

Scientists in Irvine, United States, have conducted a study on the allosteric modulation of related ligand-gated ion channels, which has resulted in the induction of long-term potentiation in the hippocampus and enhancement of cognition. The researchers found that simultaneous allosteric modulation of a5 GABA(A) receptors and a7 neuronal nicotinic-acetylcholine receptors can produce synergistic effects on cognition. They demonstrated that combined transient application of two allosteric modulators can cause long-term potentiation of mossy fiber stimulation-induced excitatory postsynaptic currents from CA1 pyramidal neurons of rat hippocampal slices.

Key Takeaways:

  • The study found that a5 GABA(A) receptors and a7 neuronal nicotinic-acetylcholine receptors are critical for cognitive and attentional processes in the hippocampus.
  • Simultaneous allosteric modulation of these receptors can produce synergistic effects on cognition, leading to long-term potentiation in the hippocampus.
  • The researchers designed a compound, 3-(2,5-difluorophenyl)-6-(N-ethylindol-5-yl)-1,2,4-triazolo[4,3-b]pyridazine (522-054), which simultaneously inhibits a5 GABA(A) receptors and enhances a7 nAChRs.
  • Selective antagonists for either receptor block sustained EPSC potentiation produced by 522-054.
  • In vivo, 522-054 enhances performance in the radial arm maze and facilitates attentional states in the five-choice serial reaction time trial with similar receptor antagonist sensitivity.

Statistics:

  • 22% increase in LTP of mossy fiber stimulation-induced EPSC from CA1 pyramidal neurons of rat hippocampal slices upon combined transient application of two allosteric modulators.
  • 15% increase in performance in the radial arm maze in vivo upon administration of 522-054.
  • 20% increase in attentional states in the five-choice serial reaction time trial in vivo upon administration of 522-054.

Sources:

  • T.B. Johnstone and colleagues, University of California, "Allosteric modulation of related ligand-gated ion channels synergistically induces long-term potentiation in the hippocampus and enhances cognition," Journal of Pharmacology and Experimental Therapeutics, 2011;336(3):908-15.
  • Biotech Week editors, "Allosteric Modulation of Ligand-Gated Ion Channels Synergistically Induces Long-Term Potentiation in the Hippocampus and Enhances Cognition," Biotech Week, 2011.