Negative allosteric modulation of mGlu7 disrupts fear memory reconsolidation and glutamatergic signaling in rat and human brain tissue

Anxiety- and stress-related disorders are amongst the most frequent neurological disorders, and efficient treatment is lacking. Metabotropic glutamate receptors (mGlu) have emerged as promising targets for intervention. Of particular interest is mGlu7, because of its expression in the lateral amygdala (LA), a region critical for fear learning. In the present study we examined the effects of the highly specific negative allosteric modulator of mGlu7 (ADX71743) on fear memory reconsolidation. Our investigation unveils that infusion in rats of ADX71743 in the LA or subcutaneously disrupts the reconsolidation of fear memories. This effect on reconsolidation was specific to the conditioned stimulus (CS), required fear memory recall, occurred in a defined time window after recall, and significantly decreased reinstatement of fear. Moreover, in ex vivo experiments, ADX71743 disinhibited glutamate release, as evidenced by increased spontaneous excitatory postsynaptic currents (EPSCs) frequency and enhanced amplitude of electrically and optogenetically evoked EPSCs at thalamus-to-LA synapses. Conversely, under high-stimulation conditions, ADX71743 attenuated transmission as demonstrated by the complete prevention of long-term potentiation (LTP) at thalamus-to-LA synapses. Finally, application of ADX71743 to human brain tissue mirrored the increased frequency of spontaneous EPSCs observed in the rat LA, underscoring translational relevance. Our findings highlight negative allosteric modulation of mGlu7 as a novel therapeutic avenue for addressing anxiety- and fear-related pathologies, bolstered by the congruent effects of ADX71743 on glutamatergic transmission across species.