Ablation of optineurin impairs metabotropic glutamate receptor 5 signaling in mouse hippocampus

Optineurin (OPTN) is a ubiquitously expressed autophagy adaptor that forms a functional interactome with Group I metabotropic glutamate receptors (mGluR1 and 5), members of the Gα q/11 protein receptor family. OPTN attenuates mGluR1 coupling to phospholipase Cβ (PLCβ) and subsequent inositol trisphosphate (IP3) formation in response to agonist stimulation. We have also demonstrated that pathological mGluR5 signaling impairs autophagic machinery via GSK3β/ZBTB16 pathway in both Alzheimer's and Huntington's disease mouse models. In this study, we investigated whether mGluR5 signaling is regulated in an OPTN‐dependent manner. We knocked out Optn gene in STHdh Q7/Q7 striatal cells using CRISPR/Cas9 approach and employed OPTN null mice to probe the impact of OPTN loss on mGluR5 canonical and autophagic signaling. We show that OPTN deletion enhances Ca 2+ mobilization following mGluR5 activation in STHdh Q7/Q7 cells and impairs mGluR5‐mediated ERK1/2 phosphorylation in both STHdh Q7/Q7 cells and acute hippocampal slices. In addition, OPTN loss enhanced basal GSK3β activity and increased the breakdown of ZBTB16 in STHdh Q7/Q7 cells, and abolished mGluR5‐mediated inactivation of GSK3β/ZBTB16 pathway in hippocampal slices. OPTN deletion also increased the expression levels of autophagy adaptor P62 in hippocampal slices, an effect that was reversed by mGluR5 antagonism. Overall, the data suggest that mGluR5 and OPTN crosstalk is essential for mGluR5 signaling and therefore can potentially contribute to the pathophysiology of neurodegenerative diseases.