Synaptic plasticity in human thalamocortical assembloids
Mary H. Patton, Kristen T. Thomas, Ildar T. Bayazitov, Kyle D. Newman, Nathaniel B. Kurtz, Camenzind G. Robinson, Cody A. Ramirez, Alexandra J. Trevisan, Jay B. Bikoff, Samuel T. Peters, Shondra M. Pruett‐Miller, Yanbo Jiang, A Schild, Anjana Nityanandam, Stanislav S. Zakharenko
Abstract
Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids. Single-nucleus RNA sequencing revealed that >80% of cells in thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits.