Synaptic plasticity in human thalamocortical assembloids

Abstract

SUMMARYSynaptic 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 most cells in mature 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.HighlightsHuman thalamic organoids consist of mostly glutamatergic projection neurons.Thalamocortical assembloids form reciprocal glutamatergic synapses.Synapses are functional and undergo short-term plasticity resembling animal models.Long-term potentiation and depression reveal mechanisms distinct from rodents.eTOCHuman organoids are often used to model diseases with synaptic pathology; however, few studies have examined synaptic function via single-cell or single-synapse recordings. Patton et al. fused human thalamic and cortical organoids into assembloids to examine synaptic transmission and short- and long-term synaptic plasticity in human thalamocortical and corticothalamic circuits.GRAPHICAL ABSTRACT

Role of Post-Transcriptional Regulation in Learning and Memory in Mammals

“…Although these events have been clearly recognized, the precise molecular factors involved are still a matter of intense study. For example, some laboratories are taking advantage of the possibility of using human-derived pluripotent stem cells in order to obtain organoids able to function as in vitro models of brain development and functions [ 39 ]. The interest devoted to LTP generation is also due to observations that indicate there are age-related differences in the ability to generate LTP, as well as variations in LTP generation, and, as a consequence, in learning and memory activities experienced in many neurodegenerative diseases [ 40 ].…”