title: Altered profile of basket cell afferent synapses in hyper-excitable dentate gyrus revealed by optogenetic and two-pathway stimulations.
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.
authors.affiliation: Experimental Epilepsy Group, Division of Neurology, Wallenberg Neuroscience Centre, Lund University Hospital, Lund, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Ledri
authors.forename: Litsa
authors.initials: L
authors.lastname: Nikitidou
authors.forename: Ferenc
authors.initials: F
authors.lastname: Erdelyi
authors.forename: Gabor
authors.initials: G
authors.lastname: Szabo
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.forename: Merab
authors.initials: M
authors.lastname: Kokaia
mesh_terms: D000818:Animals; D002766:Cholecystokinin / Q000502:physiology; D018891:Dentate Gyrus / Q000502:physiology*; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D059330:GABAergic Neurons / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D007696:Kindling, Neurologic / Q000502:physiology; D008027:Light; D051379:Mice; D008822:Mice, Transgenic; D009475:Neurons, Afferent / Q000502:physiology; D009478:Neuropeptide Y / Q000494:pharmacology* / Q000502:physiology; D018408:Patch-Clamp Techniques; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D009478:Neuropeptide Y; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D002766:Cholecystokinin