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Cellular mechanisms and cognitive roles of mossy fiber input-induced heterosynaptic plasticity in CA3 pyramidal cells : CA3 피라미드 세포에서 태상섬유 입력에 의해 유도되는 이형시냅스간 가소성의 세포기전과 인지기능에서의 역할

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의과대학 의과학과
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서울대학교 대학원
CA3 pyramidal cellKv1.2heterosynaptic plasticitypattern separation
학위논문 (박사)-- 서울대학교 대학원 : 의과학과 생리학전공, 2015. 8. 이석호.
The intrinsic excitability of neurons plays a critical role in the encoding of memory at Hebbian synapses and in the coupling of synaptic inputs to spike generation. It has not been studied whether somatic firing at physiologically relevant frequency can induce intrinsic plasticity in hippocampal CA3 pyramidal cells (CA3-PCs). A conditioning train of 20 action potentials (APs) at 10 Hz causes a persistent reduction in the input conductance and an acceleration of the AP onset time in CA3-PCs, but not in CA1-PCs. Induction of such long-term potentiation of intrinsic excitability (LTP-IE) was accompanied by a reduction in the D-type K+ current, and was abolished by the inhibition of endocytosis or protein tyrosine kinase (PTK). Consistently, the CA3-PCs from Kv1.2 (gene name, Kcna2) knock-out mice displayed no LTP-IE with the same conditioning. Furthermore, the induction of LTP-IE depended on the back-propagating APs (bAPs) and intact distal apical dendrites. These results indicate that LTP-IE is mediated by the internalization of Kv1.2 channels from the distal regions of apical dendrites, which is triggered by bAP-induced dendritic Ca2+ signaling and the consequent activation of PTK. It has been postulated that hippocampal mossy fiber (MF) inputs constrain the CA3 network to sparsely represent direct cortical inputs and thus subserve pattern separation. However, the cellular mechanism underlying this hypothesis remains elusive. Here, I show that a short tetanic stimulation of afferent MFs induces long-term potentiation (LTP) of perforant path (PP)-evoked excitatory postsynaptic potentials (PP-EPSPs) in CA3-PCs. I demonstrate that the downregulation of Kv1.2 mediates MF input-induced heterosynaptic LTP of PP-EPSPs but had little effect on recurrent synaptic inputs, because surface expression of Kv1.2 is polarized to distal apical dendrites. Rapid pattern separation was impaired in Kcna2-haploinsufficient mice, in which CA3-PCs lacked the heterosynaptic LTP, suggesting that Kv1.2 plays an essential role in pattern separation.
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