title: Mechanisms of sharp wave initiation and ripple generation.
abstract: Replay of neuronal activity during hippocampal sharp wave-ripples (SWRs) is essential in memory formation. To understand the mechanisms underlying the initiation of irregularly occurring SWRs and the generation of periodic ripples, we selectively manipulated different components of the CA3 network in mouse hippocampal slices. We recorded EPSCs and IPSCs to examine the buildup of neuronal activity preceding SWRs and analyzed the distribution of time intervals between subsequent SWR events. Our results suggest that SWRs are initiated through a combined refractory and stochastic mechanism. SWRs initiate when firing in a set of spontaneously active pyramidal cells triggers a gradual, exponential buildup of activity in the recurrent CA3 network. We showed that this tonic excitatory envelope drives reciprocally connected parvalbumin-positive basket cells, which start ripple-frequency spiking that is phase-locked through reciprocal inhibition. The synchronized GABA(A) receptor-mediated currents give rise to a major component of the ripple-frequency oscillation in the local field potential and organize the phase-locked spiking of pyramidal cells. Optogenetic stimulation of parvalbumin-positive cells evoked full SWRs and EPSC sequences in pyramidal cells. Even with excitation blocked, tonic driving of parvalbumin-positive cells evoked ripple oscillations. Conversely, optogenetic silencing of parvalbumin-positive cells interrupted the SWRs or inhibited their occurrence. Local drug applications and modeling experiments confirmed that the activity of parvalbumin-positive perisomatic inhibitory neurons is both necessary and sufficient for ripple-frequency current and rhythm generation. These interneurons are thus essential in organizing pyramidal cell activity not only during gamma oscillation, but, in a different configuration, during SWRs.
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, János Szentágothai PhD Program of Semmelweis University, H-1085 Budapest, Hungary.
authors.forename: Dániel
authors.initials: D
authors.lastname: Schlingloff
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, Faculty of Information Technology, Pázmány Péter Catholic University, H-1083 Budapest, Hungary, and.
authors.forename: Szabolcs
authors.identifier: http://orcid.org/0000-0002-2740-6057
authors.initials: S
authors.lastname: Káli
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, Faculty of Information Technology, Pázmány Péter Catholic University, H-1083 Budapest, Hungary, and.
authors.forename: Tamás F
authors.initials: TF
authors.lastname: Freund
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hájos
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, gulyas@koki.hu.
authors.forename: Attila I
authors.identifier: http://orcid.org/0000-0003-4961-636X
authors.initials: AI
authors.lastname: Gulyás
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D060848:Agatoxins / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017487:Ankyrins / Q000378:metabolism; D056654:CA3 Region, Hippocampal / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000075402:Channelrhodopsins; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010320:Parvalbumins / Q000235:genetics; D017603:Signal Detection, Psychological; D013779:Tetrodotoxin / Q000494:pharmacology; D058585:Vestibular Evoked Myogenic Potentials / Q000187:drug effects / Q000502:physiology*
chemical_list: D060848:Agatoxins; D000779:Anesthetics, Local; C094681:Ank3 protein, mouse; D017487:Ankyrins; D002121:Calcium Channel Blockers; D000075402:Channelrhodopsins; D010320:Parvalbumins; D013779:Tetrodotoxin
keywords: basket cell; current generator; hippocampus; inhibition; oscillation; rhythm