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 (mGlu2 and mGlu3) 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 mGlu3 induces long-term depression (LTD) of excitatory transmission in the PFC at inputs from the basolateral amygdala. Our data suggest mGlu3-LTD is mediated by postsynaptic AMPAR internalization in PFC pyramidal cells, and we observed a profound impairment in mGlu3-LTD following a single, 20-min restraint stress exposure. Finally, blocking mGlu3 activation in vivo prevented the stress-induced maladaptive changes to amygdalo-cortical physiology and motivated behavior. These data demonstrate that mGlu3 mediates stress-induced physiological and behavioral impairments and further support the potential for mGlu3 modulation as a treatment for stress-related psychiatric disorders.
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 (mGlu3) induces a postsynaptic form of long-term depression (LTD) that is dependent on the activity of another subtype, mGlu5. Stress exposure disrupted this plasticity, but the underlying signaling mechanisms and involvement in higher-order cognition have not yet been investigated. Acute stress was applied by 20-minutes restraint and early reversal learning was evaluated in an operant-based food-seeking task. We employed whole-cell patch-clamp recordings of layer 5 prelimbic (PL)-PFC pyramidal cells to examine mGlu3-LTD and several mechanistically distinct mGlu5-dependent functions. Acute stress impaired both mGlu3-LTD and early reversal learning. Interestingly, potentiating mGlu5 signaling with the mGlu5 positive allosteric modulator (PAM) VU0409551 rescued stress-induced deficits in both mGlu3-LTD and reversal learning. Other aspects of PL-PFC mGlu5 function were not disrupted following stress; however, signaling downstream of mGlu5-Homer interactions, phosphoinositide-3-kinase (PI3K), Akt, and glycogen synthase kinase 3β was implicated in these phenomena. These findings demonstrate that acute stress disrupts early reversal learning and PL-PFC-dependent synaptic plasticity and that potentiating mGlu5 function can restore these impairments. These findings provide a framework through which modulating coordinated mGlu3/mGlu5 signaling may confer benefits for the treatment of stress-related psychiatric disorders.
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