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Cerebellar deficits as mechanisms for motor, cognitive, and social dysfunction in Dravet syndrome

Mackenzie Howard, PhD – The University of Texas at Austin
Cerebellar deficits as mechanisms for motor, cognitive, and social dysfunction in Dravet syndrome
Research Grant – 2 years, $165,000


Grant Summary:
 In addition to frequent and severe seizures, most people with Dravet syndrome also suffer life-altering difficulties (“comorbidities”) with coordinated movement/muscle control, autism-associated behaviors, and learning and memory that continue even when their seizures are medically controlled. The cerebellum is a brain region known to be involved in movement, cognition/memory, and social behavior, but is understudied in Dravet syndrome and epilepsy in general. Our lab has new preliminary data showing that the physiology of a certain type of neurons in the cerebellum, Purkinje cells, are hypo-active in a mouse model of Dravet syndrome. Similar hypoactivity of this cell type causes movement disorders and autism in other neurological diseases. Previously, the link between Purkinje cell dysfunction and the neurological deficits of Dravet syndrome has been difficult to study due to the very early age at which Dravet syndrome mice die. However, we have bred a new mouse line in which only cerebellar Purkinje cells have the Dravet syndrome mutation. These mice survive into adulthood, begin to show changes in movement and other behaviors. We will use these mice as a new tool to study Purkinje cell function and how cerebellar dysfunction causes the changes in motor control, social behavior, and learning difficulties seen in Dravet syndrome. We will take a team approach to this problem: Dr. Howard’s lab specializes in cell physiology in Dravet syndrome and will examine Purkinje cell properties; our collaborators in Dr. Brumback’s lab specialize in autism spectrum disorder and will examine social behavior in these mice; Dr. Nishiyama’s lab specializes in the function of the cerebellum and will examine learning and memory in this neural circuit.

About the Investigator: Dr. MacKenzie Howard was a burned-out cellular neurophysiologist who found new inspiration and motivation after shifting into the field of translational epilepsy research when he joined Dr. Scott Baraban’s lab for a second postdoc. Upon starting his own lab at Dell Medical School / University of Texas at Austin, he focused his research on studying basic mechanisms of Dravet syndrome using mouse models. His primary interest is in how changes in neural information processing at the cellular level cause the ongoing cognitive, affective, and motor comorbidities that persist between seizures in Dravet syndrome.

 

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