Biology subjects

Birey, F.

Publications and source records attributed to Birey, F..

5 recordsLinked to original sources

bioRxiv2026

Human neuromodulatory assembloids to study serotonin signaling and disease

Neuromodulators influence critical functions of the developing human brain and regulate behavioral states. Dysfunction of neuromodulatory systems is often involved in neuropsychiatric disease and many drugs for these conditions act on these signaling pathways. Recent advances in stem cell biology have made it possible to derive a wide range of cells across the developing human nervous system in regionalized organoids and to functionally integrate them into assembloids, however they currently do not systematically incorporate neuromodulation. Here, we generated human midbrain-hindbrain organoids (hMHO) from human induced pluripotent stem (hiPS) cells and fused them with human cortical organoids (hCO) to form neuromodulatory assembloids (hNMA). We focus on serotonin (5-hydroxytryptamine, 5-HT) as one key neuromodulator and found characteristic gene expression patterns and electrophysiological properties of serotonergic neurons (5-HT neurons) in the hMHO. In hNMA, 5-HT neurons projected into hCO, released 5-HT and modulated cortical network activity. To explore the applicability of this system in human disease, we studied 22q11.2 deletion syndrome (22q11.2DS), a common microdeletion associated with high risk for neuropsychiatric disease and defects in 5-HT signaling. We found aberrant 5-HT dynamics in hNMA from patient hiPS cell lines that were rescued by administration of a selective serotonin reuptake inhibitor (SSRI). Taken together, hNMA can be used to study human 5-HT dynamics and uncover disease phenotypes which could facilitate therapeutic development.

neuroscience↗

bioRxiv2025

Human-specific tandem repeat in CACNA1C modulates responses to neuronal stimulation

The recent development of long-read sequencing has made it possible to catalog variable number tandem repeats (VNTRs) in the human genome. However, little is known about their functional consequences. Here, we characterized the effect of TRACT, a VNTR that is unique to humans and that has sequence variants linked to risk for bipolar disorder and schizophrenia. By adding or removing this VNTR in both mouse models and human neural organoids, we find that TRACT, which is intronic to the L-type voltage-gated calcium channel gene CACNA1C, increases intracellular calcium after neuronal stimulation and leads to widespread changes in activity-dependent transcription programs in neurons. TRACT-dependent changes are enriched for genes associated with synapse formation and plasticity, and partially recapitulate evolutionary changes in activity-dependent transcription between species. These findings demonstrate that a single, human-specific, non-coding element can strongly affect the neuronal response to stimulation, and motivate the study of VNTRs as a genetic source of phenotypic variation in both evolution and disease.

genetics↗

bioRxiv2023

Adrenomedullin promotes interneuron migration in a dual human model for hypoxic interneuronopathy of prematurity.

Extremely preterm birth (at < 28 postconceptional weeks) leads to brain injury and represents the leading cause of childhood-onset neuropsychiatric diseases. No effective therapeutics exist to reduce the incidence and severity of brain injury of prematurity. Hypoxic events are the most important environmental factor, along with inflammation. Among other developmental processes, the second half of in utero fetal development coincides with the migration of cortical interneurons from the ganglionic eminences into the cortex; this process is thus prone to disruptions following extremely preterm birth. To date, no studies have directly investigated the migration of human cortical inhibitory neurons under hypoxic conditions. Using multi-day confocal live imaging in human forebrain assembloids (hFA) derived from human induced pluripotent stem cells (hiPSCs) and ex vivo developing human brain tissue, we found a substantial reduction in the migration of hypoxic interneurons. Using transcriptomics, we identified adrenomedullin (ADM) as the gene with the highest fold change increase in expression. Based on previous literature about the protective role of supplemental ADM for other injuries, here, we demonstrated that addition of exogenous ADM to the hypoxic media restores the migration defects of interneurons. Lastly, we showed that one of the mechanisms of protection by ADM is through the activation of the cAMP/PKA pathway and subsequent pCREB-dependent rescued expression of a subset of GABA receptors, which are known to promote migration. Overall, in this manuscript we provide the first direct evidence for hypoxia-induced deficits in the migration of human cortical interneurons and identify ADM as a possible target for therapeutic development. SummaryWe identified human cortical interneurons migration deficits under hypoxic conditions and rescued this phenotype using adrenomedullin.

neuroscience↗

bioRxiv2023

Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway

Abnormalities in crosstalk between the thalamus and the cerebral cortex are thought to lead to severe neuropsychiatric disorders, such as epilepsy and psychotic disorders. Pathogenic variants in the CACNA1G gene, which encodes the 1G subunit of the thalamus-enriched T-type voltage-gated calcium channel CaV3.1, are associated with absence seizures, intellectual disability, and schizophrenia, but the cellular and circuit level consequences of these genetic variants in humans remain unknown. Here, we developed an in vitro human assembloid model of the thalamocortical pathway to systematically dissect the contribution of genetic variants in T-type calcium channels. We discovered that a CACNA1G variant (M1531V) associated with seizures led to changes in T-type currents in human thalamic neurons, as well as correlated hyperactivity of thalamic and cortical neurons in thalamo-cortical assembloids. In contrast, CACNA1G loss, which has been associated with risk of schizophrenia, resulted in abnormal thalamocortical connectivity that was related to both increased spontaneous thalamic activity and aberrant thalamic axonal projections. Taken together, these results illustrate the utility of organoid and assembloid systems for interrogating human genetic disease risk variants at both cellular and circuit level.

neuroscience↗

bioRxiv2021

Dissecting the molecular basis of human interneuron migrationin forebrain assembloids from Timothy syndrome

Defects in interneuron migration during forebrain development can disrupt the assembly of cortical circuits and have been associated with neuropsychiatric disease. The molecular and cellular bases of such deficits have been particularly difficult to study in humans due to limited access to functional forebrain tissue from patients. We previously developed a human forebrain assembloid model of Timothy Syndrome (TS), caused by a gain-of-function mutation in CACNA1C which encodes the L-type calcium channel (LTCC) Cav1.2. By functionally integrating human induced pluripotent stem cell (hiPSC)-derived organoids resembling the dorsal and ventral forebrain from patients and control individuals, we uncovered that migration is disrupted in TS cortical interneurons. Here, we dissect the molecular underpinnings of this phenotype and report that acute pharmacological modulation of Cav1.2 can rescue the saltation length but not the saltation frequency of TS migrating interneurons. Furthermore, we find that the defect in saltation length in TS interneurons is associated with aberrant actomyosin function and is rescued by pharmacological modulation of MLC phosphorylation, whereas the saltation frequency phenotype in TS interneurons is driven by enhanced GABA sensitivity and can be restored by GABA receptor antagonism. Overall, these findings uncover multi-faceted roles of LTCC function in human cortical interneuron migration in the context of disease and suggest new strategies to restore interneuron migration deficits.

neuroscience↗