Cerebellin 2 Dysregulation Mediates Synaptic Deficiency in Down Syndrome

2023 Seed Grant
Andre M. M. Sousa, Ph.D.
University of Wisconsin-Madison

Down syndrome is the most common genetic cause of intellectual disability. Intellectual disability in individuals with Down syndrome includes deficits in cognition, attention, working memory, motor development, and language that begin in the first months of life. These deficits progress with age an have significant consequences on long-term academic, occupational, and daily life outcomes. Intellectual disability is attributed to developmental defects in neurons and how they form connections between them. In fact, neurons in individuals with Down syndrome have a reduces number of connections, called synapses, and these connections are altered, thus affecting the way neurons communicate with each other. The appearance of these deficits during infancy suggests that these alterations appear during the earliest stages of brain development.
In this proposal, Dr. Sousa’s laboratory aims to gain insight into the decreased number of connections between neurons and their impaired communication in Down syndrome. They will focus on a specific gene named Cerebellin-2. This gene is critical for the formation and maintenance of connections between neurons. Dr. Sousa’s preliminary studies indicate that the levels of Cerebellin-2 in neurons of individuals with Down syndrome is greatly reduced during the critical period for the formation of connections between neurons. Thus, they hypothesize that these reduced levels of Cerebellin-2 are the cause for the deficits they observe in the number and function of these connections. Using stem cells donors with and withouth from Down syndrome, Dr. Sousa’s lab will study the impact of the reduced expression of Cerebellin-2 on the formation of connections between neurons, and will determine whether restoring the expression of Cerebellin-2 in the neurons from Down syndrome patients can reestablish a normal number of connections between neurons and their proper function. This study will advance our understanding on the molecular mechanisms that may lead to intellectual disability in Down syndrome and uncover new target for future therapeutic studies.

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