Stem cell models of human synapse development and degeneration

Abstract

Many brain disorders exhibit altered synapse formation in development or synapse loss with age. To understand the complexities of human synapse development and degeneration, scientists now engineer neurons and brain organoids from human-induced pluripotent stem cells (hIPSC). These hIPSC-derived brain models develop both excitatory and inhibitory synapses and functional synaptic activity. In this review, we address the ability of hIPSC-derived brain models to recapitulate synapse development and insights gained into the molecular mechanisms underlying synaptic alterations in neuronal disorders. We also discuss the potential for more accurate human brain models to advance our understanding of synapse development, degeneration, and therapeutic responses.

Cytoskeletal regulation of synaptogenesis in a model of human fetal brain development

“…for 3 months to capture the onset of excitatory synaptogenesis (Paşca et al, 2015;Wilson & Newell-Litwa, 2018). At this stage, HCSs are at early stages of corticogenesis and exhibit expression of the deep layer marker, ctip2, and the upper layer marker, satb2 ( Figure S2).…”

Visualizing the Synaptic and Cellular Ultrastructure in Neurons Differentiated from Human Induced Neural Stem Cells—An Optimized Protocol

“…While this allows a certain enrichment of desired cell types, a 100% pure cell type is never achieved. Adherent differentiation on coated coverslips has been the standard approach leading to immature synapse formation after less than one week and spontaneous synaptic activity after roughly one month [17]. However, a full maturity (e.g., formation of synapses on spines) is possibly not achieved.…”

“…Certain neurons form dendritic spines, highly dynamic structures for multiple synaptic contacts [24]. The timing and sequence of synaptogenesis have already been studied in the human fetus decades ago, but only recently it has been acknowledged that neurons derived from human stem cells in vitro exhibit a different timing in synaptogenesis and certain features associated with synaptic maturity (e.g., spine formation) might be absent altogether [17]. As usual, when dealing with stem cell-derived neurons, much is dependent on the individual protocol employed.…”

Human-Derived Brain Models: Windows into Neuropsychiatric Disorders and Drug Therapies

“…Since the discovery of hIPSCs, a wide array of neurological diseases has been modeled, including neurodegenerative diseases, such as AD, and neurodevelopment disorders, such as Autism Spectrum Disorders (ASDs). 8 hIPSCs have also provided a unique tool to gain insights in rare neurologic disorders, such as Kleefstra Syndrome, 9 Dravet Syndrome, 10 and Smith Lemli Opitz Syndrome. 11 These hIPSC models mimic brain development and pathology more closely than human immortal cancer cell lines and primary animal cell culture; this will likely allow for more accurate predictions of patient responses.…”

“…For example, a recent study used the propensity for brain spheroids to fuse with one another to monitor interneuron migration between brain spheroids. 8 By similarly allowing for fusion of AD and unaffected brain organoids, one could monitor the propagation of pathological features and the resulting cell death. This method can also be used to fuse brain region-specific organoids 48 and assay for drugs that block the spread of protein aggregates between brain regions.…”