NEUROPHARMACOLOGY | 卷:144 |
Mechanisms underlying prelimbic prefrontal cortex mGlu3/mGlu5-dependent plasticity and reversal learning deficits following acute stress | |
Article | |
Joffe, Max E.1,2,3  Santiago, Chiaki I.2  Stansley, Branden J.1,2  Maksymetz, James1,2  Gogliotti, Rocco G.1,2  Engers, Julie L.2  Nicoletti, Ferdinando4,5  Lindsley, Craig W.1,2,3,6  Conn, P. Jeffrey1,2,3  | |
[1] Vanderbilt Univ, Dept Pharmacol, 12475E MRB4, Nashville, TN 37232 USA | |
[2] Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN USA | |
[3] Vanderbilt Ctr Addict Res, Nashville, TN 37232 USA | |
[4] Univ Sapienza Roma, Dept Physiol & Pharmacol, I-00185 Rome, Italy | |
[5] IRCCS Neuromed, Pozzilli, Italy | |
[6] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA | |
关键词: Stress; Prelimbic prefrontal cortex; mGlu(3); mGlu(5); Synaptic plasticity; Reversal learning; | |
DOI : 10.1016/j.neuropharm.2018.10.013 | |
来源: Elsevier | |
【 摘 要 】
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(3)) induces a postsynaptic form of long-term depression (LTD) that is dependent on the activity of another subtype, mGlus. 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 mGlu(3)-LTD and several mechanistically distinct mGlus-dependent functions. Acute stress impaired both mGlu(3)-LTD and early reversal learning. Interestingly, potentiating mGlus signaling with the mGlus positive allosteric modulator (PAM) VU0409551 rescued stress-induced deficits in both mGlu(3)-LTD and reversal learning. Other aspects of PL-PFC mGlu(5) function were not disrupted following stress; however, signaling downstream of mGlu(5)-Homer interactions, phosphoinositide-3-kinase (PI3K), Akt, and glycogen synthase kinase 3 beta was implicated in these phenomena. These findings demonstrate that acute stress disrupts early reversal learning and PL-PFC-dependent synaptic plasticity and that potentiating mGlus function can restore these impairments. These findings provide a framework through which modulating coordinated mGlu(3)/mGlus signaling may confer benefits for the treatment of stress-related psychiatric disorders.
【 授权许可】
Free
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
10_1016_j_neuropharm_2018_10_013.pdf | 1950KB | download |