195 Aberrant Brain Biomechanics Initiates Ventricular Dilation in a Genetic Subtype of Congenital Hydrocephalus

Abstract

INTRODUCTION: We have previously shown using human genetics and mouse models that TRIM71 is a bona fide disease gene causing human congenital hydrocephalus. Disease-associated mutations in TRIM71 disrupt neural stem cell proliferation, however how these developmental effects physiologically lead to ventricular dilation is not clear. METHODS: We developed a number of novel methods to characterize cerebrospinal fluid (CSF) circulation, including cilia-generated currents and bulk flow. We then used these methods to comprehensively characterize CSF dynamics and intracranial physiology in hydrocephalic Trim71R595H/+ mice that harbor the same point mutation found in human hydrocephalus patients. RESULTS: We found that in hydrocephalic Trim71R595H/+ mice, impaired neurogenesis results in a hypoplastic cerebrocortical wall that exhibits loss of stiffness and elasticity. This leads to a floppy hypercompliant state wherein the brain parenchyma is unable to hold the pressure exerted by CSF, thereby facilitating passive pooling of CSF and secondary distention of the ventricles. Ventriculomegaly occurs in the absence of altered cilia-generated CSF flow or congenital aqueductal obstruction. Neuroimaging studies in patients with TRIM71 mutations also suggest cortical hypoplasia as the primary physiological factor leading to secondary ventricular dilation and passive pooling of CSF. CONCLUSIONS: We highlight the importance of precisely regulated neural stem cell fate and neurogenesis for maintaining normal brain-CSF biomechanical interactions that limit ventricular expansion. We thus demonstrate that some or potentially many forms of CH are in fact a congenital brain malformation akin to microcephaly with secondarily enlarged ventricles rather than a primary disturbance in CSF circulation.