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Titel: The role of Arc/Arg3.1 in hippocampal synaptic plasticity in adulthood and during early postnatal development
Sonstige Titel: Die Rolle von Arc/Arg3.1 in der hippokampalen synaptischen Plastizität im Erwachsenenalter und während der frühen postnatalen Entwicklung
Sprache: Englisch
Autor*in: Xompero, Francesca
Schlagwörter: Synaptische Plastizität; Langzeitpotenzierung; Langzeitdepression; unmittelbar-früh exprimierte Gene Arc/Arg3.1; synaptic plasticity; hippocampus; immediate early gene (IEG); Arc/Arg3.1; long term memory; long term potentiation (LTP); long term depression (LTD)
GND-Schlagwörter: Hippocampus; Nervenzelle; Langzeitgedächtnis; Plastizität; Gen
Erscheinungsdatum: 2018
Tag der mündlichen Prüfung: 2018-07-02
Zusammenfassung: 
Memory is a critical brain function essential for the encoding, storage, and retrial of information. The hippocampus has a central role in the processing of semantic, episodic and emotional memories. Over the last decades, evidence suggested that synaptic plasticity is the cellular model underlying memory formation. Long-term potentiation (LTP) and long-term depression (LTD) are the most studied forms of synaptic plasticity in the hippocampus and they can be induced by electrical, chemical or sensory experiences. Arc/Arg3.1 is an immediate early gene discovered to be involved in the consolidation of memory as well as in the maintenance of LTP and LTD. In my PhD-work, I was interested to study the cellular mechanisms of synaptic plasticity underlying memory formation in Arc/Arc/3.1-deficient mice. First I established a novel form of LTD and studied the cellular mechanisms underlying LTD induction and maintenance in acute hippocampal slices of adult mice. Next, I investigated the novel form of LTD in Arc/Arg3.1 deficient mice (KO). KO showed an exaggerated early phase of LTD (E-LTD) but the size of the late phase of LTD (L-LTD) was comparable to the L-LTD in WT. This novel form of LTD was dependent on NMDARs activation both in WT and KO. In WT, the LTD maintenance was supported by novel protein synthesis and lysosomal degradation. In contrast, the LTD in KO was independent of both novel protein synthesis and lysosomal degradation, despite the same size as the L-LTD in WT. One of the key features of Arc/Arg3.1 gene is that following transcription, Arc/Arg3.1 mRNA can be delivered to the dendrites where it undergoes local translation. Interestingly, the LTD induced in slices from mice lacking the local translation of Arc/Arg3.1 mRNA (tg) failed to consolidate. Together these results might recognize the local Arc/Arg3.1 mRNA translation as the essential process for the expression of the LTD in adulthood.
It was shown that Arc/Arg3.1 is already expressed in the hippocampus and the forebrain already early after birth. Arc/Arg3.1 mRNA is detected at P7 with upregulation peak between P14 and P21. In order to study whether the early Arc/Arg3.1 expression influences adult plasticity, two conditional mouse lines were generated. Early cKO mice, in which arc/Arg3.1 was ablated after P7, exhibited an enhanced E-LTD but the size of the L-LTD was comparable to the L-LTD of the control group. The LTD induced in late cKO mice, in which Arc/Arg3.1 was ablated after P21, did not differ from the LTD of the control group. Furthermore, the LTD in late cKO mice was protein synthesis independent. Together these results might suggest that the presence of Arc/Arg3.1 early during development affects the E-LTD. Meanwhile, Arc/Arg3.1 is essential in adulthood to couple long-lasting plasticity to novel protein synthesis, eventually leading to memory formation. Additionally, I was also interested to investigate LTP in Arc/Arg3.1 deficient mice. Two forms of LTP were studied, one form induced by high-frequency stimulation (HFS) and the second by theta burst stimulation (TBS). HFS-LTP was induced in KO, early and late cKO mice and, despite the literature on the fundamental role of Arc/Arg3.1 in the consolidation of synaptic plasticity, the HFS-LTP remained stable throughout the entire recordings in all genotypes and no differences in the magnitude were found compared to the control groups. These results might suggest that the strong stimulation generated by the high-frequency overcame the necessity of Arc/Arg3.1 in the consolidation of this form of plasticity. The independence of the novel protein synthesis in HFS-LTP of KO and late cKO mice also corroborated the hypothesis previously proposed that the Arc/Arg3.1 is essential in adulthood for coupling long-lasting synaptic plasticity to protein synthesis underlying memory. Lastly, TBS-LTP was shown to be exaggeratedly induced in KO but lacked the ability to consolidate. In late cKO mice, in contrast, TBS-LTP did not differ from the TBS-LTP of the control group. Thus, these results demonstrated that the presence of Arc/Arg3.1 early postnatally is essential to establish proper neuronal transmission in order to sustain TBS-induced plasticity.
Taking together, the results of my PhD work suggest that Arc/Arg3.1 deficient mice, under certain circumstances, are able to undergo and maintained activity-dependent synaptic plasticity. Nevertheless, this capability does not act in linking synaptic plasticity and memory consolidation. The cellular mechanisms which support the abnormal long-lasting plasticity in KO mice remain still unknown.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/7770
URN: urn:nbn:de:gbv:18-92331
Dokumenttyp: Dissertation
Betreuer*in: Kuhl, Dietmar (Prof. Dr.)
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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