UCLA

ABSTRACT OF THE DISSERTATION

Investigating the Role for Dysbindin in Hippocampal-Dependent Learning and Memory: Glutamatergic Mechanisms

By

Bryant Lance Horowitz

Doctor of Philosophy in Psychology

University of California, Los Angeles, 2012

Professor J. David Jentsch, Chair

Schizophrenia is a complexly defined disorder with many genes contributing to the high heritability, but the degree to which these genes contribute to the pathophysiology is unclear. DTNBP1, which codes for the dysbindin protein, has been identified as one of the candidate risk genes in schizophrenia. Dysbindin is one of eight proteins that make up the biogenesis of lysosome-related organelles complex 1(BLOC-1), which includes pallidin, muted, snapin, cappuccino, and BLOC-1 subunits 1, 2, and 3.The BLOC-1 complex is involved in trafficking of vesicles. Variation in DTNBP1 has been associated with increased risk of schizophrenia in behavioral genetic studies of humans, as well as deficits in cognition and memory phenotypes. Studies on the physiology of the dysbindin protein reveal reduction in expression within forebrain glutamatergic neurons, playing a role in trafficking of vesicles in the BLOC-1 complex. The sandy mouse, which carries a mutation of the DTNBP1 gene and does not code for the dysbindin protein, has been used to study behavioral, cellular and physiological processes; revealing compromised glutamatergic neurotransmission and deficits in working memory and cognitive function similar to patients with schizophrenia. Sandy mice were used to examine hippocampal-dependent tasks of memory. Homozygous sandy mice showed normal locomotor movement and some learning in a Morris water maze task compared to heterozygous and wild type controls, but were impaired in spatial memory. Sandy mice also showed deficits in recognition memory and contextual memory compared to heterozygous and wild type controls. To investigate the role of dysbindin as BLOC-1 dependent the pallid mouse, which has a null mutation in the Pldn gene which produces no pallidin protein, was examined in context and recognition memory tasks and showed deficits in fear generalization and recognition memory; but not identical to deficits shown in sandy mice. Taken together, this data indicates that dysbindin may be acting independently of BLOC-1.