Anatomy and physiology of molecular layer heterotopia

The National Institute of Neurological Disorders and Stroke (NINDS) awarded New York Institute of Technology $459,000 under the Extramural Research Programs in the Neurosciences and Neurological Disorders (CFDA 93.853) program. The award, effective July 12, 2025, through June 30, 2028, funds a three-year research project investigating the anatomy and physiology of molecular layer heterotopia (MLH), a neuronal migration defect characterized by misplaced neurons in neocortical layer I. Using GPR56 knockout mice that exhibit MLH identical to human presentations, the research will employ spatial transcriptomics, quantitative microscopy techniques, and in vivo calcium imaging to characterize neuronal and glial cellular changes associated with heterotopia and test whether these malformations result in hyper-excitable neuronal circuits underlying seizures and cognitive deficits.

The project addresses a significant gap in understanding MLH despite its association with multiple neurodevelopmental disorders including dyslexia, epilepsy, cobblestone lissencephaly, Fukuyama muscular dystrophy, and GPR56 polymicrogyria. Beyond the primary research deliverables, the award includes training and educational components designed to prepare undergraduate and osteopathic medical students in developmental neuroscience for potential graduate studies or careers in biomedical science. The findings are expected to advance treatment development strategies for individuals affected by neocortical malformations and associated cognitive and neurological impairments.

Abstract

Abstract neocortical malformations due to defective neuronal migration are often associated with epilepsy and life-long cognitive impairment. Therefore, understanding the anatomical and physiological changes accompanying neocortical malformations are important for the development and design of novel treatments for affected individuals. Molecular layer heterotopia (MLH) are neuronal migration defects characterized by collections of misplaced neurons in layer i and are observed in numerous neurodevelopmental disorders including: dyslexia, epilepsy, cobblestone lissencephaly, fukuyama muscular dystrophy, and GPR56 polymicrogyria. Surprisingly, little is known about the cellular mechanisms and physiological changes associated with MLH despite the variety of disorders and clinical presentations associated with heterotopia. Studies in mice with identical MLH to those observed in humans offer the potential to develop a greater understanding of MLH. Thus, the proposed studies will use GPR56 knockout mice with MLH to describe the neuronal and glial changes that accompany heterotopia using spatial transcriptomics and quantitative microscopy techniques. In vivo calcium imaging in GPR56 knockout mice crossed to calcium-indicator mice will be used to test the hypothesis that heterotopia result in hyper- excitable neuronal circuitry changes that underlie seizures and cognitive deficits. Finally, the proposed work will provide exciting research opportunities that will train undergraduate and osteopathic medical students in developmental neuroscience to prepare them for possible graduate studies or future careers in biomedical science.