0017 ABNORMAL SLEEP SPINDLE RHYTHMOGENESIS IN MICE BEARING A SCHIZOPHRENIA ASSOCIATED CODING VARIANT IN THE CACNA1I GENE

Abstract

Sleep-spindles are waxing and waning EEG oscillations (10 - 15 Hz), that are characteristic of NREM-sleep. Sleep-spindles are generated when GABAergic reticular thalamic nucleus (TRN) neurons release a barrage of inhibition onto thalamocortical neurons. This inhibitory barrage is caused by ‘rebound bursting’ of the TRN neurons and is mediated by low-threshold ‘T-Type’ Ca channels. CACNA1I encodes CaV3.3 T-type calcium channels and its expression is enriched in TRN. Sleep-spindles are associated with cognitive deficits of schizophrenia (Wamsley et al., 2013). CACNA1I is a schizophrenia risk gene, and de novo missense variations (R1346H) has been identified in schizophrenia proband in trio sequencing. Rebound bursting and sigma power (the frequency band of sleep-spindles) during NREM-REM transitions is diminished in mice lacking CaV3.3 (Astori et al., 2011). R1346H is expected to alter sleep EEG patterns akin to the Cav3.3 knock-out animals because R1346H reduces the whole-cell current density of CaV3.3 channels in vitro, likely by impairing trafficking of the channel to the membrane surface (Andrade et al., 2016). However, the effect of this mutation on sleep spindles has yet to be assessed. We have produced mouse models and recorded EEG in CaV3.3-KO mice, R1305H knock-in mice (homologous to the human R1346H) and their wild-type littermates. We here report our initial characterization of these mice in sleep architecture, sleep-spindle density and sigma power during NREM-REM transition. Cav3.3-KO and R1305H-Cav3.3 mice displayed abnormalities in sleep-spindle density compared to WT. The time spent in NREM-sleep did not differ between WT, Cav3.3-KO or R1305H-Cav3.3 mice. The schizophrenia risk gene CACNA1I may play a role in a specific aspect of sleep physiology that is known to be impaired in schizophrenia. R21 MH099448, Stanley Research Foundation (Pan) R01 NS098505, Stanley Research Foundation (Zhang & Feng) VA Merit Grant (McCarley, I01BX001356) VA Merit Grant (Strecker, I01BX002774) NIMH R01 MH039683 (McCarley) VA CDA 1IK2BX002130 (McNally) NINDS, R01NS098505(Feng).