Induction of long-term potentiation and depression phenomena in human induced pluripotent stem cell-derived cortical neurons.

A. Odawara, H. Katoh, N. Matsuda, I. Suzuki 
Volume 469, Issue 4, 22 January 2016, Pages 856–862

Highlights
•HFS induced LTP and LTD phenomena in hiPSC-derived cortical neurons.
•Spike patterns were generated or disappeared in induction of plasticity.
•hiPSC-derived neurons express the spike pattern with a precise timing change.
•HFS induced L-LTP-like plasticity and the change of synchronized burst firing.
•MEA system is beneficial for clarifying the function of hiPSC-derived neurons.

Abstract
Plasticity such as long-term potentiation (LTP) and long-term potentiation depression (LTD) in neuronal networks has been analyzed using in vitro and in vivo techniques in simple animals to understand learning, memory, and development in brain function. Human induced pluripotent stem cell (hiPSC)-derived neurons may be effectively used for understanding the plasticity mechanism in human neuronal networks, thereby elucidating disease mechanisms and drug discoveries. In this study, we attempted the induction of LTP and LTD phenomena in a cultured hiPSC-derived cerebral cortical neuronal network using multi-electrode array (MEA) systems. High-frequency stimulation (HFS) produced a potentiated and depressed transmission in a neuronal circuit for 1 h in the evoked responses by test stimulus. The cross-correlation of responses revealed that spike patterns with specific timing were generated during LTP induction and disappeared during LTD induction and that the hiPSC-derived cortical neuronal network has the potential to repeatedly express the spike pattern with a precise timing change within 0.5 ms. We also detected the phenomenon for late-phase LTP (L-LTP) like plasticity and the effects for synchronized burst firing (SBF) in spontaneous firings by HFS. In conclusion, we detected the LTP and LTD phenomena in a hiPSC-derived neuronal network as the change of spike pattern. The studies of plasticity using hiPSC-derived neurons and a MEA system may be beneficial for clarifying the functions of human neuronal circuits and for applying to drug screening.

神經(jīng)可塑性如長時程增強（LTP）和長時程增強抑制（LTD）在神經(jīng)網(wǎng)絡(luò)中的機制，及種種關(guān)于學(xué)習(xí)、記憶，及發(fā)育等腦功能發(fā)展已通過不同動物模型，使用離體和載體等技術(shù)來分析研究。人類誘導(dǎo)多能干細(xì)胞衍生的神經(jīng)元（hiPSC-NC）可以有效地用于理解人類神經(jīng)網(wǎng)絡(luò)的可塑性機制，從而闡明疾病發(fā)病機制和幫助藥物研發(fā)。在這項研究中，日本東北工業(yè)大學(xué)的研究人員試圖采用多電極陣列（MEA）系統(tǒng)在培養(yǎng)的hiPSC皮層神經(jīng)元誘導(dǎo)LTP和LTD現(xiàn)象。高頻刺激（HFS）在神經(jīng)元電路產(chǎn)生一組長達(dá)一小時的增效和抑制傳遞的誘發(fā)反應(yīng)。相關(guān)的相應(yīng)反應(yīng)顯示，具有特別時間值的峰電位模式在LTP的誘導(dǎo)中產(chǎn)生，并于LTD誘導(dǎo)中消失，hiPSC-衍生的皮質(zhì)神經(jīng)元網(wǎng)絡(luò)有可能重復(fù)地表達(dá)該峰電位，時間精確度可達(dá)到0.5 ms內(nèi)。研究人員也檢測到類似可塑性的后期LTP現(xiàn)象（L-LTP）和類似HFS的自發(fā)電位發(fā)射中的同步簇狀發(fā)射（SBF）的結(jié)果。研究人員觀察到在hiPSC衍生的神經(jīng)元網(wǎng)絡(luò)的LTP和LTD現(xiàn)象伴隨峰電位模式變化。使用hiPSC衍生神經(jīng)元和MEA系統(tǒng)可幫助研究人員研究人類神經(jīng)元電路的功能和藥物篩選的可塑性研究。