Normal Pressure Hydrocephalus in Adult Mice Causes Gait Impairment, Cognitive Deficits, and Urinary Frequency with Incontinence

Abstract

Normal pressure hydrocephalus (NPH) is marked by enlarged cerebral ventricles with normal intracranial pressure, plus three stereotypical symptoms: gait impairment, cognitive dysfunction, and urinary frequency with urge-incontinence. The neural circuit dysfunction responsible for each of these symptoms remains unknown, and an adult mouse model would expand opportunities to explore these mechanisms in preclinical experiments. Here, we describe the first mouse model of chronic, communicating hydrocephalus with normal intracranial pressure. Hydrocephalic male and female mice had unsteady gait and reduced maximum velocity. Despite performing well on a variety of behavioral tests, they exhibited subtle learning impairments. Hydrocephalic mice also developed urinary frequency, and many became incontinent. This mouse model, with symptoms resembling human NPH, can be combined with molecular-genetic tools in any mouse strain to explore the neural circuit mechanisms of these symptoms. Preclinical work using this hydrocephalus model will lead to the development of new treatments for NPH symptoms.Significance StatementLike human patients with normal pressure hydrocephalus (NPH), mice with communicating hydrocephalus develop enlarged cerebral ventricles with normal intracranial pressure plus three stereotypical symptoms: gait impairment, cognitive dysfunction, and urinary frequency with incontinence. This mouse model, with symptoms resembling human NPH, can be combined with molecular-genetic tools in any mouse strain to explore neural circuit mechanisms of NPH symptoms.