| dc.description.abstracteng | Memory encoding is thought to proceed from durable changes in the activity of synaptic circuits, leading to the storage of patterns of electrical events in a sparsely distributed ensemble of neurons. Located at the entry level of hippocampal circuitry, the CA3 region is thought to be important for episodic memory encoding, especially at the initial stage of acquisition, by presumably developing an instant representation of a context. CA3 pyramidal cells receive a variety of inputs, among which the mossy fiber (Mf) inputs draw special attention for their peculiar structure and unique synaptic properties. However, the links between the plasticity of CA3 circuits and memory encoding are not well understood.
This thesis project aimed to address the synaptic mechanisms of episodic memory encoding in physiological conditions as well as in a mouse model of Alzheimer's disease (AD).
AD is characterized at an early stage by impaired episodic memory, which may involve dysregulation of the plasticity of CA3 circuits.
First of all, we searched for synaptic deficits in CA3 local circuit in the early stage of AD pathology in acute slices, taking advantage of a familial AD mouse model: 6-month male APP/PS1 mice. We report that there is a reduction in spontaneous IPSC frequency in CA3 pyramidal cells (PCs) together with decreased inhibitory charges of evoked events at Mf-CA3 synapses, whereas the short-term plasticity of these synapses and intrinsic properties of CA3 PCs remain unaffected. Furthermore, there is a robust reduction in Kainate receptor (KAR) mediated currents at Mf-CA3 synapses. The same results were obtained from PSKO mice, suggesting that disturbed function of γ-secretase and N-Cadherin processing pathways may underlie the dysfunction of KARs at Mf-CA3 synapses.
In the next step, we explored the changes in CA3 circuits shortly after one-trial contextual fear conditioning in adult C57Bl6j mice. We show that despite hardly any changes in filopodia number of Mf terminals, an increase in spontaneous IPSC
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frequency can be registered, while the EPSCs and short-term plasticities of these synapses are unaltered. However, this increase cannot be seen anymore 24 hours after the contextual learning. We also tried to do simplified computational modeling of the DG-CA3 neuronal networks, to investigate if and to what extent the local interneurons in CA3 region contribute to memory encoding precision.
Finally, to screen for changes at a transcriptome level, we performed RNA-seq with dissected CA3 tissue from APP/PS1 mice and identified up- and down-regulated genes at this early stage of AD. Moreover, we carried out ChIP-seq for a histone modification marker: H3K4me3, which has been shown to be directly related to one-trial contextual memory, and we report that there is a significant decrease in H3K4me3 levels at the promoter areas of various genes in CA3 PCs. However, these genes are hardly overlapping with the down-regulated genes from RNA-seq result, suggesting that other epigenetic mechanisms may play more important roles in expressing early deficits in this AD mouse model.
Taken together, we show that inhibitory connections of hippocampal CA3 circuits may be important for episodic memory encoding, and in early AD mouse model with memory deficits, there is reduced GABAergic transmission and reduced KAR-mediated currents in CA3 PCs, together with many active transcriptional regulations across the genome. Our study may contribute to the understanding of early AD pathologies at a synaptic level as well as a transcriptional level, and provide novel insights into the mechanisms underlying rapid encoding of contextual memory. | de |