ArticleBiological psychiatry2024
TCF4 Mutations Disrupt Synaptic Function Through Dysregulation of RIMBP2 in Patient-Derived Cortical Neurons.
Article in Biological psychiatry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 17 citations in OpenAlex.
- Temporal Transcriptional Regulation of Human Neuronal Differentiation via Forward Programming.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- Decomposing genetic effects of social connectedness and depression on youth behaviors and long-term clinical outcomes.medRxiv : the preprint server for health sciences · 2025Article
- Single-cell profiling identifies hair cell SLC35F1 deficiency as a signature of primate cochlear aging.Nature aging · 2025Article
- Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics.Neuron · 2025Article
- Tcf4 Deficiency causes recurrent seizures in mice.Progress in neurobiology · 2025Article
- A novel human organoid model system reveals requirement of TCF4 for oligodendroglial differentiation.Life science alliance · 2025Article
- Transcription factor 4 expression in the developing non-human primate brain: a comparative analysis with the mouse brain.Frontiers in neuroanatomy · 2024Article
- MicroRNA-495 Modulates Neuronal Layer Fate Determination by TargetingInternational journal of biological sciences · 2024Article
- Psychiatric risk gene Transcription Factor 4 (TCF4) regulates the density and connectivity of distinct inhibitory interneuron subtypes.Molecular psychiatry · 2023Article
- Genome-Wide Association Study and Rare Variant Association Studies of Strabismus in theOphthalmology scienceArticle
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18 authors at 3 institutions in 1 country.
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Abstract
backgroundGenetic variation in the TCF4 (transcription factor 4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of autism spectrum disorder called Pitt-Hopkins syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models has been shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking.
methodsTo model PTHS, we differentiated human cortical neurons from human induced pluripotent stem cells that were derived from patients with PTHS and neurotypical individuals. To identify pathophysiology and disease mechanisms, we assayed cortical neurons with whole-cell electrophysiology, Ca
resultsCortical neurons derived from patients with TCF4 mutations showed deficits in spontaneous synaptic transmission, network excitability, and homeostatic plasticity. Transcriptomic analysis indicated that these phenotypes resulted in part from altered expression of genes involved in presynaptic neurotransmission and identified the presynaptic binding protein RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons.
conclusionsTaken together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.
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