Emily M. Parker - US grants

PROJECT SUMMARY/ABSTRACT Schizophrenia (Sz) is a chronic illness with prominent synaptic pathology and a leading cause of disability. Dendritic spine density is reduced in Sz in layer III of primary auditory cortex (A1). Spine loss in A1 in Sz is thought to underlie auditory sensory processing deficits and in turn contribute to socio-cognitive dysfunction, which is associated with the poorest functional outcomes among individuals with Sz. Recently our lab determined that spine reductions in A1 in Sz are selective for loss of small, presumably new dendritic spines. The goal of this training fellowship is to explore a potential molecular mechanism for small dendritic spine loss, like observed in A1 in Sz. Our lab recently demonstrated that small spine loss in A1 is associated with increased levels of the ? subunit, an auxiliary subunit of voltage gated calcium channels (VGCCs). ? subunits regulate the activity of VGCCs: they promote surface expression of channel-forming subunits, regulate channel gating, and facilitate Gbl-, RGK-, phospho- and lipid-mediated inhibition. Overexpressing CACNB4, which encodes ?4, reduced small, but not large spines in vitro, proof-of-concept that increased ?4 levels could drive the small spine loss observed in A1 in Sz. ?4 is a candidate protein for the loss of small, presumably new dendritic spines in A1 in Sz. Auxiliary subunits differentially regulate high voltage activated (HVA) and low voltage activated (T- type) VGCCs. Emerging evidence suggests that ? subunits can interact with and gate T-type VGCCs25-28. Blocking T-type but not HVA VGCCs impeded the assembly of new dendritic spines2. The experiments in this proposal will test the hypothesis that small spine loss is due to ?4-mediated decrease in T-type VGCC function and impaired new spine assembly. During this training fellowship I will receive excellent training in Sz neurobiology, cell and slice culture, patch clamp electrophysiology, Ca2+ and live cell imaging methods from experts in the field. Even if I am not able to accept my central hypothesis, these data collected from these experiments will provide novel and important information about the regulation of T-type VGCCs and ?4 modulation of spine dynamics. Additionally, these data have the potential to inform the development of innovative pharmacological interventions for auditory processing deficits and socio-cognitive dysfunction in Sz.