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The Dendritic NMDA Spike As a Fundamental Mechanism Initiating Associative Plasticity in the CA3 Region of the Hippocampus

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The Dendritic NMDA Spike As a Fundamental Mechanism Initiating Associative Plasticity in the CA3 Region of the Hippocampus Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2016 The dendritic NMDA spike as a fundamental mechanism initiating associative plasticity in the CA3 region of the hippocampus Brandalise, Federico Abstract: A major goal in neuroscience is to understand how changes in synaptic strength allow neurons to store information. A related question concerns the mechanisms through which neurons distinguish between relevant and non-relevant input. It is in fact a general assumption that a neuronal stimulus would have a significant impact on the surrounding network only in the case in which it will provide a depolarization, on a postsynaptic neuron, sufficient to exceed the action potential threshold. This concept is hardly applicable in brain regions such as the dentate gyrus of the hippocampus, which ex- hibits exceptionally sparse activity that rarely elicits action potentials in targeted CA3 pyramidal cells. It is thus unclear how weak input from the dentate granule cells, which represents a major conduit of information to the hippocampus, sustains adequate levels of synaptic plasticity for memory storage in the CA3 network. For my doctoral project, I have assessed the functional consequences of mossy fiber input to the hippocampal CA3 network, a matrix-like structure implicated in pattern completion and navigational learning. Repetitive pairing of a synaptic response mediated by the recurrent fibers that interconnect CA3 pyramidal cells and of a subsequent subthreshold mossy fiber response induced long-term potentiation (LTP) at the CA3 recurrent synapses in rat hippocampus in vitro. Reversing the timing of the inputs induced long-term depression (LTD). Investigation of the mechanism underly- ing this form of input- timing-dependent synaptic plasticity (ITDP) revealed that the giant excitatory postsynaptic potential evoked by mossy fiber stimulation enhanced glutamatergic current at activated CA3 recurrent synapses by relieving magnesium block from NMDA receptor channels. Furthermore, the repetitive pairing protocol frequently led to the generation of localized supralinear dendritic responses, whose probability of induction correlated with the magnitude of LTP. Candidate mechanisms for active dendritic responses are sodium spikes, calcium spikes, and NMDA spikes. Experiments with pharmaco- logical blockers allowed us to rule out a role for sodium or calcium spikes and identified NMDA spikes as the source of the supralinear dendritic signals associated with LTP. We then designed experiments to provide evidence for a causal relationship between the generation of NMDA spikes and associative LTP. Using a combination of dendritic recording and calcium imaging we were able to show that NMDA spikes evoke regenerative branch-specific calcium transients that are critical for LTP induction. Moreover, we examined the role of back-propagating spikes and found that a burst of back-propagating action poten- tials, but not a single back-propagating action potential, can lead to the generation of an NMDA spike. In conclusion, our data indicate that the current textbook paradigm positing the back-propagating action potential as the ultimate effector for LTP induction is incorrect. Instead, our experiments showthat NMDA spikes are necessary and sufficient to produce the critical postsynaptic depolarization required for associative LTP between hippocampal pyramidal cells and this event can be triggere both under subthreshold input (ITDP) and suprathreshold responses (STDP). Eines der Hauptziele der Neurowis- senschaft ist zu verstehen, wie Unterschiede in der Synapsenstärke neuronaler Schaltkreise es erlauben Information zu speichern. In diesem Zusammenhang ist es wichtig die Mechanismen zu verstehen, durch welche Neuronen in der Lage sind zwischen wichtigen und unwichtigen synaptischen Eingängen zu un- terscheiden. Es wird weitgehend angenommen, dass ein exzitatorischer synaptischer Eingang nur dann einen signifikanten Einfluss hat, wenn er zu einer Depolarisierung führt, welche ein Aktionspotential in- duziert. Diese Annahme trifft jedoch wahrscheinlich nicht für die Körnerzellen des Gyrus dentatus zu, deren ausserordentlich spärliche Aktivität nur selten ein Aktionspotential in den CA3 Pyramidenzellen auslöst. Daher ist es ungewiss, wie die schwachen Signale der Körnerzellen, welche den Hauptsignal- weg von Informationen zum Hippocampus bilden, genügend synaptische Plastizität für die Speicherung von Gedächtnisinhalten im CA3-Netzwerk entfalten können. Für mein Dissertations-Projekt habe ich die funktionellen Auswirkungen der Aktivierung von Moosfasern, den Axonen der Körnerzellen, auf das hippocampale CA3-Netzwerk im Detail erforscht. Die Struktur des CA3-Netzwerkes ähnelt einer Ma- trix und dient vor allem der Komplettierung von Mustern sowie der Navigation. Wiederholtes Paaren von synaptischen Antworten, ausgelöst durch die Stimulation von rekurrenten CA3 Fasern, gefolgt von unterschwelligen Moosfaserantworten, induzierten im Hippocampus in vitro eine Langzeitpotenzierung (LTP) an den rekurrenten CA3-Synapsen. Die Umkehr der Stimulationssequenz führte, hingegen, zu einer Langzeitdepression (LTD). Genauere Nachforschungen über den Mechanismus dieser zeit- und se- quenzabhängigen synaptischen Plastizität (ITDP) zeigten, dass die starken exzitatorischen postsynap- tischen Potentiale, welche durch die Stimulation von Moosfasern ausgelöst wurden, die Antworten an rekurrenten CA3-Synapsen durch die Aufhebung der Magnesiumblockade von NMDA-Rezeptorkanälen verstärken. Darüber hinaus hat dieses wiederholte Paarungsprotokoll vermehrt zu der Entstehung von lokalen, supralinearen dendritischen Antworten geführt. Deren Wahrscheinlichkeit einer Entstehung kor- relierte mit der Stärke der LTP. Mögliche Auslöser von aktiven, dendritischen Antworten sind Natrium-, Kalzium- oder NMDA-Spikes. Unsere Experimente mit pharmakologischen Inhibitoren ermöglichten uns Natrium- und Kalzium-Spikes auszuschliessen und NMDA-Spikes als Ursache für die supralinearen, den- dritischen Signale zu identifizieren, welche mit der LTP assoziiert sind. Wir haben daher Experimente entworfen, um den Beweis für einen kausalen Zusammenhang zwischen der Entstehung von NMDA- Spikes und der assoziierten LTP zu erbringen. Durch die Kombination von dendritischen Ableitungen mit bildgebenden Verfahren zur Messung von Kalziumsignalen konnten wir zeigen, dass die NMDA-Spikes in den Dendritenästen regenerierende, Ast-spezifische Kalziumströme auslösen, welche für die Induktion von LTP essenziell sind. Zusätzlich haben wir die Rolle der Backpropagation von Aktionspotentialen untersucht. Dabei stellte sich heraus, dass kurze Salven, jedoch nicht einzelne, backpropagating Ak- tionspotentiale einen NMDA-Spike auslösen können. Zusammenfassend lässt sich sagen, dass unsere Daten den aktuellen Wissensstand über Backpropagation von Aktionspotentialen als Auslöser einer LTP mindestens für das CA3 Gebiet des Hippocampus widerlegen. Mit unseren Versuchen konnten wir zeigen, dass NMDA-Spikes sowohl notwendig wie auch ausreichend sind, um die entscheidende, postsynaptische Depolarisierung auszulösen, welche für die assoziative LTP zwischen den CA3 Pyramidenzellen des Hip- pocampus erforderlich ist. Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-149585 Dissertation Published Version Originally published at: Brandalise, Federico. The dendritic NMDA spike as a fundamental mechanism initiating associative plasticity in the CA3 region of the hippocampus. 2016, University of Zurich, Faculty of Science. 2 The Dendritic NMDA Spike as a Fundamental Mechanism Initiating Associative Plasticity in the CA3 Region of the Hippocampus Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von FEDERICO BRANDALISE aus Italien Promotionskomitee Prof. Dr. Urs Gerber Prof. Dr. Fritjof Helmchen (Vorsitz) Prof. Dr. Kevan Martin Zürich, 2016 1 “One cell to rule them all, and in the dendrites bind them” Rui P. Costa and P. Jesper Sjöström 2 TABLE OF CONTENT ABSTRACT…………………………………………………………………………… 5 ZUSAMMENFASSUNG…………………………………………………………... 7 INTRODUCTION………………………………………………………………….... 9 INDUCTION OF SYNAPTIC PLASTICITY…………………………………… 10 ACTIVE DENDRITIC SIGNALING……………………………………………. 16 DENDRITIC SPIKES IN CA3 PYRAMIDAL CELLS………………………… 19 NMDA SPIKES AND LTP……………………………………………………… 23 BRANCH-SPECIFIC LTP AND HOMEOSTATIC PLASTICITY …………… 24 RESULTS………………………………………………………………………............ 27 MOSSY FIBER-EVOKED SUBTHRESHOLD RESPONSES INDUCE TIMING-DEPENDENT PLASTICITY AT HIPPOCAMPAL CA3 RECURRENT SYNAPSES; PNAS, 2014……………………………………. 29 Summary………………………………………………………………… 30 Introduction……………………………………………………………… 30 Results…………………………………………………………………… 31 Discussion……………………………………………………………….. 50 Materials and Methods…………………………………………………. 52 Bibliography……………………………………………………………… 54 DENDRITIC NMDA SPIKES ARE NECESSARY FOR TIMING- DEPENDENT ASSOCIATIVE PLASTICITY IN THE HIPPOCAMPUS; Nat. Communications, 2016………………………………. 61 Summary…………………………………………………………………. 62 Introduction………………………………………………………………. 62 Results……………………………………………………………………. 63 Discussion……………………………………………………………….. 86 Materials and Methods…………………………………………………. 87 Bibliography……………………………………………………………… 94 3 Acknowledgments ……………………………………………………… 100 Author contributions………..……………………..…………………….. 100 CONDITIONING BY SUBTHRESHOLD SYNAPTIC INPUT CHANGES THE CHARACTERISTIC
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