Metabotropic glutamate receptors (mGluRs), heptahelical transmembrane receptors coupled to G-proteins, contribute to the regulation of neuronal excitability and synaptic transmission¹. Genes coding for eight mGluRs (denoted mGluR1-8) with different splice variants have been identified and classified into three groups based on sequence homology, pharmacology, and signaling pathways. Group I mGluRs (mGluR1 and mGluR5) are primarily located postsynaptically. Group II (mGluR2 and mGluR3) are present both postsynaptically and presynaptically outside the release site. Group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8) couple to G_αi/o to inhibit adenylyl cyclase found in the presynaptic active zone².

The mGluR8 receptor is detected in the olfactory bulb, thalamus, pontine gray, cerebral cortex, hippocampus, cerebellum, and retina³. Electrophysiological studies suggest that mGluR8 functions as a presynaptic autoreceptor to regulate glutamate release from the lateral perforant path terminals in the mouse dentate gyrus⁴. It is suggested that mGluR8, like other group III mGluRs, controls glutamate release by inhibiting voltage-gated Ca²⁺ channels.

Targeted deletion of the mGluR8 gene in mice produces subtle behavioral alterations such as reduced habituation to novelty, hyperactivity, context-dependent but not cue-dependent disruption of the freezing response in the fear conditioning test, and increased anxiety⁵.