Frontal cortex genetic ablation of metabotropic glutamate receptor subtype 3 (mGlu) impairs postsynaptic plasticity and modulates affective behaviors.

Clinical and translational studies suggest that prefrontal cortex (PFC) dysregulation is a hallmark feature of several affective disorders. Thus, investigating the mechanisms involved in the regulation of PFC function and synaptic plasticity could aid in developing new medications. In recent years, the mGlu and mGlu subtypes of metabotropic glutamate (mGlu) receptors have emerged as exciting potential targets for the treatment of affective disorders, as mGlu antagonists exert antidepressant-like effects across many rodent models.

mGlu and mGlu Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu) and 3 (mGlu) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu or mGlu potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu or mGlu NAM rapidly activated biophysically unique PFC pyramidal cell ensembles.

Mechanisms underlying prelimbic prefrontal cortex mGlu/mGlu-dependent plasticity and reversal learning deficits following acute stress.

Stress can precipitate or worsen symptoms of many psychiatric illnesses. Dysregulation of the prefrontal cortex (PFC) glutamate system may underlie these disruptions and restoring PFC glutamate signaling has emerged as a promising avenue for the treatment of stress disorders. Recently, we demonstrated that activation of metabotropic glutamate receptor subtype 3 (mGlu) induces a postsynaptic form of long-term depression (LTD) that is dependent on the activity of another subtype, mGlu.

Metabotropic glutamate receptor subtype 3 gates acute stress-induced dysregulation of amygdalo-cortical function.

Stress can precipitate or worsen symptoms of many psychiatric disorders by dysregulating glutamatergic function within the prefrontal cortex (PFC). Previous studies suggest that antagonists of group II metabotropic glutamate (mGlu) receptors (mGlu and mGlu) reduce stress-induced anhedonia through actions in the PFC, but the mechanisms by which these receptors act are not known. We now report that activation of mGlu induces long-term depression (LTD) of excitatory transmission in the PFC at inputs from the basolateral amygdala.