GABAERGIC INTERNEURON DEFICITS IN A MOUSE MODEL OF CORNELIA DE LANGE SYNDROME
Ivory Paulk1, Rosaysela Santos2, Shimako Kawauchi2, Laura Ochikubo2, Arthur Lander2, Anne Calof2.
1Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, 2University of California, Irvine, Irvine, CA.
Cornelia de Lange syndrome (CdLS) is a multi-system birth defects disorder, caused in the majority of cases by mutation in one allele of the NIPBL gene. In addition, individuals with CdLS exhibit a number of neurological disorders including mirocephaly, propensity to seizures, repetitive behaviors, mental retardation, loss of hearing, and behaviors that fall within the autism spectrum. However the cellular and molecular etiology of these deficits is largely unknown. Recently, we have developed a mouse model of CdLS (Nipbl+/- mice) that exhibits many of the neurological and behavioral deficits associated with the human disorder, and preliminary data suggest that the number of GABAergic inhibitory interneurons is decreased in the brains of these mice. There are several subtypes of GABAeric inhibitory interneurons that play a role in these various processes; they can be distinguished by co-expression of GABA-synthetic enzymes and neuropeptides such as parvalbumin and somatostatin. Since our Nipbl+/- mouse shows a high frequency of seizure upon exposure to anesthetic agents, we hypothesize that the distribution and/or number of the different subtypes of GABAgeric interneurons may be altered in different brain regions of these mice. We will test this hypothesis using a combination of methods including immunohistochemistry, in situ hybridization, and a Gad67-GFP transgenic reporter and quantify each sub-type of these neurons to identify specifically the affected region in the Nipbl+/- brain. The results of this research may lead to a better understanding of interneuron contribution to the neurological and behavioral deficits associated with CdLS and, thus, to more directed therapies for these problems.