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Inner hair cell (IHC) Ca v 1.3 Ca 2+  channels are multifunctional channels mediating Ca 2+  influx for exocytosis at ribbon synapses, the generation of Ca 2+  action potentials in pre-hearing IHCs and gene expression. IHCs of deaf systemic Ca v 1.3-deficient (Ca v 1.3 -/- ) mice stay immature because they fail to up-regulate voltage- and Ca 2+ -activated K +  (BK) channels but persistently express small conductance Ca 2+ -activated K +  (SK2) channels. In pre-hearing wildtype mice, cholinergic neurons from the superior olivary complex (SOC) exert efferent inhibition onto spontaneously active immature IHCs by activating their SK2 channels. Because Ca v 1.3 plays an important role for survival, health and function of SOC neurons, SK2 channel persistence and lack of BK channels in systemic Ca v 1.3 -/-  IHCs may result from malfunctioning neurons of the SOC. Here we analyze cochlea-specific Ca v 1.3 knockout mice with green fluorescent protein (GFP) switch reporter function,  Pax2::cre;Cacna1d-eGFP  flex/flex   and Pax2::cre;Cacna1d-eGFP  flex/- . Profound hearing loss, lack of BK channels and persistence of SK2 channels in  Pax2::cre;Cacna1d-eGFP  flex/-  mice recapitulated the phenotype of systemic Ca v 1.3 -/-  mice, indicating that in wildtype mice, regulation of SK2 and BK channel expression is independent of Ca v 1.3 expression in SOC neurons. In addition, we noticed dose-dependent GFP toxicity leading to death of basal coil IHCs of  Pax2::cre;Cacna1d-eGFP  flex/flex  mice, likely because of high GFP concentration and small repair capacity. This and the slower time course of  Pax2 -driven Cre recombinase in switching two rather than one  Cacna1d-eGFP flex   allele lead us to study  Pax2::cre;Cacna1d-eGFP  flex/-  mice. Notably, control  Cacna1d-eGFP flex/-   IHCs showed a significant reduction in Ca v 1.3 channel cluster sizes and currents, suggesting that the intronic construct interfered with gene translation or splicing. These pitfalls are likely to be a frequent problem of many genetically modified mice with complex or multiple gene-targeting constructs or fluorescent proteins. Great caution and appropriate controls are therefore required.

Cochlea-Specific Deletion of Cav1.3 Calcium Channels Arrests Inner Hair Cell Differentiation and Unravels Pitfalls of Conditional Mouse Models