Diminished Ca2+ Signaling, CaV1 Channel Expression, and Activity in Pancreatic Beta Cells Expressing Mutated DISC1 (Disrupted in Schizophrenia 1)

In addition to cognitive impairment, schizophrenics often suffer from non-obese T2D. Here, we examined whether similar cellular changes occur in pancreatic beta-cells as found in neurons from a genetic model of schizophrenia. Specifically we tested whether beta-cells exhibit disrupted excitation-secretion coupling when a truncated human DISC1 (thDISC1) gene, originally discovered in a Scottish family having high penetrance for schizophrenia, is expressed selectively in mouse beta-cells upon ingesting doxycycline (+DOX). Expression of thDISC1 significantly decreases blood insulin levels and GSIS from isolated mouse islets, revealing an independent role for DISC1 in beta-cells. In central neurons, DISC1 regulates Ca 2+ Ca V 2 channel expression, Ca 2+ influx and transmitter release. To determine whether DISC1 similarly regulates Ca 2+ physiology in beta-cells, we tested thDISC1 DOX+ vs. DOX- beta-cells for changes in: i) intracellular Ca 2+ signaling using Fluo 3-AM; ii) Ca V 1 channel expression, the dominant channel class controlling GSIS; iii) and Ca V 1 channel activity using whole-cell recording methods. We found increases in [Ca 2+ ] i following 20 mM glucose were delayed >2 min and diminished ∼50% in dissociated beta-cells expressing thDISC1. When sections of pancreas were stained with an anti-Ca V 1.2/1.3 antibody, thDISC1 DOX+ vs. DOX- insulin-positive cells exhibited decreased staining. Lastly, both peak inward Ba 2+ current and FPL 64176 induced long-lasting L-type tail current decreased significantly in thDISC1 DOX+ vs. DOX- beta-cells. No obvious change in activation kinetics was observed. These changes in excitation-secretion coupling parallel those in neurons expressing truncated DISC1. Thus at the cellular level, truncated DISC1 precipitates disorders of secretion such as schizophrenia and T2D. Disclosure P. Lu: None. R.B. Sharma: None. L.C. Alonso: None. R. Zhuge: None. A.R. Rittenhouse: None. A. Jurczyk: None.