Optogenetic control of mGluR1 signaling modulates synaptic plasticity and cerebellum driven learning

Abstract Neuronal plasticity underlying cerebellar learning behavior is strongly associated with type 1 metabotropic glutamate receptor (mGluR1) signaling. This receptor is located at perisynaptic sites at cerebellar Purkinje cells (PCs) and detects glutamate spill over. Activation of mGluR1 leads to activation of the Gq/11 pathway, inducing synaptic plasticity at the parallel fiber-Purkinje cell synapse (PF-PC) in form of long-term depression (LTD). To optogenetically modulate mGluR1 signaling we fused mouse melanopsin (OPN4) that activates the Gq/11 pathway to the C-termini of mGluR1 splice variants (OPN4-mGluR1a and OPN4-mGluR1b). We provide the prove-of-concept approach to modulate synaptic plasticity via optogenetic activation of OPN4-mGluR1a inducing LTD at the PF-PC synapse in vitro . Moreover, we demonstrate that light activation of mGluR1a signaling pathway by OPN4-mGluR1a in PCs leads to an increase in intrinsic activity of PCs in vivo and improved cerebellum driven learning behavior.