Optogenetic activation of mGluR1 signaling in the cerebellum induces synaptic plasticity

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 Gq/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 Gq/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

Optogenetic activation of mGluR1 signaling in the cerebellum induces synaptic plasticity

Neuronal plasticity underlying cerebellar learning behavior is strongly associated with type 1 $\underline {metabotropic}$ $\underline {glutamate}$ $\underline {receptor}$ (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 $\underline {melanopsin}$ (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 $Ca^{2+}$ increase in HEK cells and PCs of cerebellar slices. We provide the prove-of-concept approach to modulate synaptic plasticity via $\underline {optogenetic}$ activation of OPN4-mGluR1a inducing LTD at the PF-PC synapse $\textit {in vitro}$. Moreover, we demonstrate that light activation of mGluR1a $\underline {signaling}$ $\underline {pathway}$ by OPN4-mGluR1a in PCs leads to an increase in intrinsic activity of PCs $\textit {in vivo}$ and improved cerebellum driven learning behavior