Role of mGlu5 Receptors and Inhibitory Neurotransmission in M1 Dependent Muscarinic LTD in the Prefrontal Cortex: Implications in Schizophrenia

被引：21

作者：

Ghoshal, Ayan ^{[1
,2
]}

Moran, Sean P. ^{[1
]}

Dickerson, Jonathan W. ^{[1
]}

Joffe, Max E. ^{[1
]}

Grueter, Brad A. ^{[1
]}

Xiang, Zixiu ^{[1
]}

Lindsey, Craig W. ^{[1
]}

Rook, Jerri M. ^{[1
]}

Conn, P. Jeffrey ^{[1
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Dept Pharmacol, Nashville, TN 37240 USA

[2] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

来源：

ACS CHEMICAL NEUROSCIENCE | 2017年 / 8卷 / 10期

关键词：

positive allosteric modulators; prefrontal cortex; mGluR; muscarinic; long-term depression; schizophrenia; LONG-TERM DEPRESSION; POSITIVE ALLOSTERIC MODULATORS; METABOTROPIC GLUTAMATE RECEPTORS; SUBTYPE; 5; GROUP-I; COGNITIVE SYMPTOMS; PHENCYCLIDINE; ACTIVATION; NMDA; PARVALBUMIN;

D O I：

10.1021/acschemneuro.7b00167

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Selective potentiation of the mGlu(5) subtype of metabotropic glutamate (mGlu) receptor using positive allosteric modulators (PAMs) has robust cognition-enhancing effects in rodent models that are relevant for schizophrenia. Until recently, these effects were thought to be due to potentiation of mGlu(5)-induced modulation of NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity. However, "biased" mGlu(5) PAMs that do not potentiate mGlu(5) effects on NMDAR currents show efficacy that is similar to that of prototypical mGlu(5) PAMs, suggesting that NMDAR-independent mechanisms must be involved in these actions. We now report that synaptic activation of mGlu(5) is required for a form of long-term depression (mLTD) in mouse prefrontal cortex (PFC) that is induced by activation of M-1 muscarinic acetylcholine (mAChR) receptors, which was previously thought to be independent of mGlu(5) activation. Interestingly, a biased mGlu(5) PAM, VU0409551, that does not potentiate mGlu(5) modulation of NMDAR currents, potentiated induction of mLTD. Furthermore, coactivation of mGlu(5) and M-1 receptors increased GABA(A)-dependent inhibitory tone in the PFC pyramidal neurons, which likely contributes to the observed mLTD. Finally, systemic administration of the biased mGlu(5) PAM reversed deficits in mLTD and associated cognitive deficits in a model of cortical disruption caused by repeated phencyclidine exposure that is relevant for schizophrenia and was previously shown to be responsive to selective M-1 muscarinic receptor PAMs. These studies provide exciting new insights into a novel mechanism by which mGlu(5) PAMs can reverse deficits in PFC function and cognition that is independent of modulation of NMDAR currents.

引用

页码：2254 / 2265

页数：12

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