Biology subjects

Petter, O.

Publications and source records attributed to Petter, O..

3 recordsLinked to original sources

bioRxiv2025

Direct pathway bias and altered striatal neurogenesis in human iPSC models of 16p11.2 CNVs: Evidence from single-cell and functional analyses

Striatal medium spiny neurons (MSNs) control motor, cognitive, and social domains via direct (dMSNs) and indirect (iMSNs) basal ganglia pathways. Recent genomic analyses implicate striatal circuit dysfunction in neurodevelopmental disorders (NDDs) and highlight MSNs as a newly recognised cell type affected in schizophrenia, yet much NDD research still focuses on cortical interneurons and glutamatergic neurons, leaving MSN involvement understudied. Here, we use human iPSC-derived MSNs to demonstrate high-fidelity striatal development and explore 16p11.2 copy number variants (CNVs) - mutations predisposing carriers to autism spectrum disorder, schizophrenia, intellectual disability and other NDD conditions featuring basal ganglia deficits. By profiling both 16p11.2 duplication and deletion MSNs, we uncover reciprocal changes in MSN neurogenesis kinetics that converge on a dMSN fate bias. These shifts correspond to altered calcium signalling and enhanced firing upon direct-pathway activation. Our findings reveal a previously unappreciated role for MSN subtype imbalances in NDD pathogenesis and open new avenues for therapeutic intervention.

neuroscience↗

bioRxiv2024

Transcriptomic disruption and functional hypoactivity in DYT-SGCE MGE-patterned inhibitory neurons

Myoclonus Dystonia is a dystonic movement disorder caused by SGCE mutations, the underlying pathophysiology for which remains unclear. Here, we evaluated the impact of SGCE mutations on medial ganglionic eminence (MGE)-derived GABAergic neurons using patient-derived induced pluripotent and gene edited embryonic stem cell lines, each compared to their isogenic wild-type control. No significant differences were observed in markers of neuronal development however, single-cell RNA sequencing demonstrated transcriptomic dysregulation in genes related to axonal organization, synaptic signalling, and action potential generation in the SGCE -mutation harbouring neurons. Functional assays demonstrated reduced neurite outgrowth, lower calcium responses to GABA, and decreased neuronal excitability and network activity in the SGCE -mutant neurons. These findings contrast with the hyperexcitable phenotype previously observed in SGCE -mutant cortical glutamatergic neurons. Collectively, this supports loss of neuronal inhibitory activity, and disruption to the neuronal excitatory/inhibitory balance in motor circuits, in contributing to the overall hyperkinetic clinical phenotype in Myoclonus Dystonia.

neuroscience↗

bioRxiv2021

Dysregulation of NRSF/REST via EHMT1 is association with psychiatric disorders

Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.

neuroscience↗