Mechanisms underlying prelimbic prefrontal cortex mGlu3/mGlu5-dependent plasticity and reversal learning deficits following acute stress

Abstract

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-min 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.

Keywords: Prelimbic prefrontal cortex; Reversal learning; Stress; Synaptic plasticity; mGlu(3); mGlu(5).