Neurodevelopment: The Neurovascular Continuum*

The DEAD-box family of RNA helicases is critical for neurodevelopment. We have previously shown that variants in the DEAD-box encoding gene EIF4A2 lead to a neurodevelopmental disorder characterized by intellectual disability, epilepsy, hypotonia and cerebral structural changes. However, the mechanisms by which EIF4A2 alters neurodevelopment remain largely unknown. EIF4A2 is an essential regulator of protein translation, interacting with multiple genes during development, including several essential for interneuron differentiation and migration. These interactions suggest EIF4A2 also serves a critical role in interneuron development. To understand the importance of EIF4A2 in neurodevelopment, we created eif4a2-/- zebrafish with CRISPR/Cas9 gene editing. Since individuals with EIF4A2 variants have epilepsy and motor delays, we assessed hyperexcitability and motor function in wild type vs. eif4a2-/- zebrafish. Eif4a2-/- zebrafish exhibit hyperexcitability and motor impairments similar to individuals with pathogenic variants in EIF4A2. Preliminary data suggest that this neurodevelopmental disorder may be secondary to loss of GABA interneurons.

Stroke and cerebrovascular risk factors for poor brain health in children are not static conditions. We will discuss the major cerebrovascular issues in children and how they impact neurodevelopment over time. Cerebral hemodynamics, white matter integrity, and strategies to mitigate brain injury will be reviewed.

Understanding the pathophysiology of ischemic stroke risk, mortality, and functional loss is critical to the development of new therapies. Age and sex have a complex and interactive effect on ischemic stroke risk and pathophysiology. Aging is the strongest nonmodifiable risk factor for ischemic stroke, and aged stroke patients have higher mortality and morbidity and poorer functional recovery than their young counterparts. Early in life, the burden of ischemic stroke is higher in men, but stroke becomes more common and debilitating for women in elderly populations. Here, we review current knowledge on the influence of age and sex in the incidence, mortality, and functional outcome of ischemic stroke in clinical populations. We also discuss the experimental evidence for sex and age differences in stroke pathophysiology and how a better understanding of these variables can improve clinical care and enhance development of novel therapies.

This presentation will give a brief background regarding the contribution of cerebellar dysfunction to neurodevelopmental disorders. Subsequently, we will outline the development of a synthetic model of cerebellar cortical dysfunction that allows for the temporal manipulation of cerebellar output through inducible silencing of Purkinje cells. We will examine how the developmental timing of silencing impacts mouse behavior across domains and how the timing of cerebellar cortical dysfunction may lead to baseline differences cerebellar nuclear firing properties, thus defining a critical period for the establishment of cerebello-cortical communication.