The effect of alterations of schizophrenia-associated genes on gamma band auditory steadystate responses

Recent GWAS have identified more than 100 risk genes for schizophrenia (SCZ) [1]. Many of these encode ion channels. While their function has been well characterized, the contributions of common variation in these channels to SCZ pathology remain elusive. Here, we explored the effects of altered kinetics of voltage-gated ion channels on gamma range auditory steady-state (ASSR) deficits, a common biomarker for SCZ [2]. We used a network model of coupled E and I neurons [3].We modified the parameters of single cells in a way that mimics the expected effects of common variants associated with SCZ [4, 5].We included a total of 86 variants of the following genes: CACNA1C, CACNA1D, CACNB2, SCN1A, and HCN1 [5]. We then simulated a click train paradigm with stimulation at 40 Hz, to investigate gamma ASSR deficits. Overall, not surprisingly, we found that almost all genetic variants had a small effect on gamma power (72/86 had gamma power change<15%). However, we identified few variants that either strongly reduced or strongly increased gamma power. Interestingly, these were exclusively variants of genes encoding Ca currents subunits. Furthermore, the variants resulting in reduced gamma power also produced a strong component in the theta range. These changes in spectral composition were caused by changes in the offset and the slope of parameter ‘m’ of the high-voltage activated Ca channel. Our results deepen the understanding of gamma range ASSR deficits in patients suffering from SCZ. All scripts will be freely available (https://github.com/ChristophMetzner) and integrated into the ASSRUnit software package [6].