Synaptic plasticity in human thalamocortical assembloids

Cell Rep. 2024 Aug 27;43(8):114503. doi: 10.1016/j.celrep.2024.114503. Epub 2024 Jul 16.

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.

Keywords: CP: Neuroscience; LTD; LTP; brain organoid; cortical organoid; hiPSC; synaptic plasticity; synaptic transmission; thalamic organoid; thalamocortical.

MeSH terms

  • Cerebral Cortex / cytology
  • Cerebral Cortex / physiology
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Long-Term Potentiation / physiology
  • Neuronal Plasticity* / physiology
  • Neurons / metabolism
  • Neurons / physiology
  • Organoids / metabolism
  • Synapses / metabolism
  • Synapses / physiology
  • Thalamus* / cytology
  • Thalamus* / physiology