Biology subjects

Corea, M.

Publications and source records attributed to Corea, M..

3 recordsLinked to original sources

bioRxiv2026

Precocious maturation and Purkinje cell dysfunction in the mouse Chd8 haploinsufficient cerebellum

The cerebellum plays an emerging, but understudied, role in neurodevelopmental disorders (NDDs). Mutations in CHD8 cause a monogenic NDD (CHD8-NDD) characterized by autism and other manifestations, and prior work in Chd8 mutant mice reported cerebellar abnormalities, raising the possibility of cerebellar contribution to CHD8-NDD. To comprehensively characterize the impact of Chd8 haploinsufficiency on cerebellar development and function, we profiled the postnatal day 12 (P12) cerebellum of germline Chd8+/- mice using transcriptomic, morphological, and electrophysiological approaches. Gross cerebellar morphology was unaffected, but single-nucleus RNA sequencing revealed transcriptomic signatures of pathophysiology across cell types, including accelerated maturation of molecular layer interneurons and granule cells, and altered myelination state of oligodendrocytes. Purkinje cells (PCs) showed the strongest transcriptomic burden of any cell type and, consistent with this, exhibited altered morphology and electrophysiological properties. Bulk RNA sequencing confirmed that transcriptomic pathology persists into adulthood, indicating lasting impacts on both neuronal and glial gene expression. Together, these results capture cell-type-specific cerebellar perturbations associated with Chd8 haploinsufficiency and support the cerebellum as a relevant site of pathology in CHD8-NDD.

neuroscience↗

bioRxiv2025

Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice.

CHD8 mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. Chd8+/- mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nucleus transcriptomics (snRNA-seq), we found increased Chd8+/- cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive Chd8+/- and conditional Camk2a-Cre Chd8+/-mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found Chd8+/-mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, Chd8 haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.

genomics↗

bioRxiv2024

Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments and neurobehavioral phenotypes including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the WAC gene. Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures. However, no thorough studies from a vertebrate model exist to understand how these changes occur. To overcome this, we developed both murine and zebrafish Wac/wac deletion mutants and studied whether their phenotypes recapitulate those described in individuals with DESSH syndrome. We first show that the two Wac models exhibit craniofacial and behavioral changes, reminiscent of abnormalities found in DESSH syndrome. In addition, each model revealed impacts to GABAergic neurons and further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors. Finally, we uncovered transcriptional impacts of Wac loss of function in mice that will pave the way for future molecular studies into DESSH. These studies present two new animals that begin to uncover some biological underpinnings of DESSH syndrome and elucidate the biology of Wac.

neuroscience↗