STIM1 Controls Neuronal Ca2+ Signaling, mGluR1-Dependent Synaptic Transmission, and Cerebellar Motor Behavior

In central mammalian neurons, activation of metabotropic glutamate receptor type1 (mGluR1) evokes a complex synaptic response consisting of IP3 receptor-dependent Ca2+ release from internal Ca2+ stores and a slow depolarizing potential involving TRPC3 channels. It is largely unclear how mGluR1 is linked to its downstream effectors. Here, we explored the role of stromal interaction molecule 1 (STIM1) in regulating neuronal Ca2+ signaling and mGluR1-dependent synaptic transmission. By analyzing mouse cerebellar Purkinje neurons, we demonstrate that STIM1 is an essential regulator of the Ca2+ level in neuronal endoplasmic reticulum Ca2+ stores. Both mGluR1-dependent synaptic potentials and IP3 receptor-dependent Ca2+ signals are strongly attenuated in the absence of STIM1. Furthermore, the Purkinje neuron-specific deletion of Stim1 causes impairments in cerebellar motor behavior. Together, our results demonstrate that in the mammalian nervous system STIM1 is a key regulator of intracellular Ca2+ signaling, metabotropic glutamate receptor-dependent synaptic transmission, and motor coordination. •STIM1 is strongly expressed in cerebellar Purkinje neurons•STIM1 controls endoplasmic reticulum Ca2+ stores in Purkinje neurons•STIM1 regulates mGluR1/TRPC3-dependent slow excitatory synaptic potentials•Selective deletion of STIM1 in Purkinje neurons impairs cerebellar motor behavior By analyzing cerebellar Purkinje neuron-specific mouse mutants, Hartmann et al. demonstrate that STIM1 is a key regulator of intracellular neuronal calcium signaling that determines metabotropic glutamate receptor-dependent synaptic transmission and cerebellar motor behavior.