Optogenetic activation of mGluR1 signaling in the cerebellum induces synaptic plasticity

Highlights

• Optogenetic tools modulate splice variant-specific mGluR1 signaling

• Activation of OPN4-mGluR1 variants induce Gq-mediated intracellular Ca²⁺ increase

• Proof-of-concept approach to modulate synaptic plasticity via OPN4-mGluR1a

• OPN4-mGluR1 activation bolsters intrinsic activity and cerebellum driven learning

Summary

Neuronal plasticity underlying cerebellar learning behavior is strongly associated with type 1 metabotropic glutamate receptor (mGluR1) signaling. Activation of mGluR1 leads to activation of the G_q/11 pathway, which is involved in 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 G_q/11 pathway to the C-termini of mGluR1 splice variants (OPN4-mGluR1a and OPN4-mGluR1b). Activation of both OPN4-mGluR1 variants showed robust Ca²⁺ increase in HEK cells and PCs of cerebellar slices. 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.