Publications by authors named "Mayuri V Thete"
Article Synopsis
- Researchers studied neural circuits in the brain important for sensorimotor processing and their links to neuropsychiatric disorders using advanced methods involving human pluripotent stem cells.
- They created specialized four-part "loop assembloids" that mimic key brain regions, allowing for the observation of synchronized neuronal activity and connectivity.
- This platform is valuable for investigating genetic influences on disorders like autism and Tourette syndrome, revealing unique patterns of neuronal behavior associated with these conditions.
Article Synopsis
- Abnormal thalamocortical communication can result in neuropsychiatric disorders, with specific genetic variants in the CACNA1G gene linked to conditions like absence seizures, intellectual disability, and schizophrenia.
- Researchers created a human assembloid model to study the effects of CACNA1G variants on thalamocortical pathways, discovering that a specific variant (M1531V) altered calcium currents in thalamic neurons and increased activity in both thalamic and cortical neurons.
- Conversely, the loss of CACNA1G was found to disrupt thalamocortical connectivity, leading to heightened spontaneous activity in thalamic neurons and abnormal axon projections, highlighting the importance of multi-cellular models in understanding
Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A.
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- The study focuses on creating human ascending somatosensory assembloids (hASA) from pluripotent stem cells to model the human spinothalamic pathway, which is crucial for transmitting pain and sensory information to the brain.
- Researchers confirmed the presence of important cell types in the hASA using transcriptomic profiling and demonstrated connections between sensory neurons and thalamic neurons through rabies tracing and calcium imaging.
- Experiments showed that chemical stimulation led to coordinated neuronal responses, and the disruption of the sodium channel SCN9A, associated with pain insensitivity, affected the synchrony of the network, highlighting the potential of this model for understanding sensory pathways and developing pain therapies
The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain, which has been challenging to study at inaccessible stages of late gestation and early postnatal human development. Autism spectrum disorder and other neurodevelopmental disorders (NDDs) have been associated with abnormal cortical interneuron development, but which of these NDD genes affect interneuron generation and migration, and how they mediate these effects remains unknown. We previously developed a platform to study interneuron development and migration in subpallial organoids and forebrain assembloids.
View Article and Find Full Text PDFDefects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration of cortical and ventral forebrain organoids, we have previously discovered a cortical interneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmental disease caused by a mutation in the L-type calcium channel (LTCC) Ca1.2.
View Article and Find Full Text PDFNeurons in the cerebral cortex connect through descending pathways to hindbrain and spinal cord to activate muscle and generate movement. Although components of this pathway have been previously generated and studied in vitro, the assembly of this multi-synaptic circuit has not yet been achieved with human cells. Here, we derive organoids resembling the cerebral cortex or the hindbrain/spinal cord and assemble them with human skeletal muscle spheroids to generate 3D cortico-motor assembloids.
View Article and Find Full Text PDFCortico-striatal projections are critical components of forebrain circuitry that regulate motivated behaviors. To enable the study of the human cortico-striatal pathway and how its dysfunction leads to neuropsychiatric disease, we developed a method to convert human pluripotent stem cells into region-specific brain organoids that resemble the developing human striatum and include electrically active medium spiny neurons. We then assembled these organoids with cerebral cortical organoids in three-dimensional cultures to form cortico-striatal assembloids.
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