Altered Profile of Basket Cell Afferent Synapses in Hyper-Excitable Dentate Gyrus Revealed by Optogenetic and Two-Pathway Stimulations

Eur J Neurosci. 2012 Jul;36(1):1971-83. doi: 10.1111/j.1460-9568.2012.08080.x. Epub 2012 Apr 18.

Abstract

Cholecystokinin (CCK-) positive basket cells form a distinct class of inhibitory GABAergic interneurons, proposed to act as fine-tuning devices of hippocampal gamma-frequency (30-90 Hz) oscillations, which can convert into higher frequency seizure activity. Therefore, CCK-basket cells may play an important role in regulation of hyper-excitability and seizures in the hippocampus. In normal conditions, the endogenous excitability regulator neuropeptide Y (NPY) has been shown to modulate afferent inputs onto dentate gyrus CCK-basket cells, providing a possible novel mechanism for excitability control in the hippocampus. Using GAD65-GFP mice for CCK-basket cell identification, and whole-cell patch-clamp recordings, we explored whether the effect of NPY on afferent synapses to CCK-basket cells is modified in the hyper-excitable dentate gyrus. To induce a hyper-excitable state, recurrent seizures were evoked by electrical stimulation of the hippocampus using the well-characterized rapid kindling protocol. The frequency of spontaneous and miniature excitatory and inhibitory post-synaptic currents recorded in CCK-basket cells was decreased by NPY. The excitatory post-synaptic currents evoked in CCK-basket cells by optogenetic activation of principal neurons were also decreased in amplitude. Interestingly, we observed an increased proportion of spontaneous inhibitory post-synaptic currents with slower rise times, indicating that NPY may inhibit gamma aminobutyric acid release preferentially in peri-somatic synapses. These findings indicate that increased levels and release of NPY observed after seizures can modulate afferent inputs to CCK-basket cells, and therefore alter their impact on the oscillatory network activity and excitability in the hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholecystokinin / physiology
  • Dentate Gyrus / physiology*
  • Electric Stimulation
  • Evoked Potentials / physiology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • GABAergic Neurons / physiology
  • Green Fluorescent Proteins / genetics
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology*
  • Kindling, Neurologic / physiology
  • Light
  • Mice
  • Mice, Transgenic
  • Neurons, Afferent / physiology
  • Neuropeptide Y / pharmacology*
  • Neuropeptide Y / physiology
  • Patch-Clamp Techniques
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*

Substances

  • Neuropeptide Y
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Cholecystokinin