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Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity

Abstract

The intrinsic properties of neurons that enable them to maintain depolarized, persistently activated states in the absence of sustained input are poorly understood. In short-term memory tasks, individual prefrontal cortical (PFC) neurons can maintain persistent action potential output during delay periods between informative cues and behavioral responses. Dopamine and drugs of abuse alter PFC function and working memory, possibly by modulating intrinsic neuronal properties. Here we used patch-clamp recording of layer 5 PFC pyramidal neurons to identify a postsynaptic depolarization that was evoked by action potential bursts and mediated by metabotropic glutamate receptor 5 (mGluR5). This depolarization occurred in the absence of recurrent synaptic activity and was reduced by a dopamine D1 receptor (D1R) protein kinase A pathway. After behavioral sensitization to cocaine, the depolarization was substantially diminished and D1R modulation was lost. We propose that burst-evoked intrinsic depolarization is a form of short-term cellular memory that is modulated by dopamine and cocaine experience.

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Figure 1: Patch-clamp recording from layer 5 pyramidal PFC neurons showing mGluR-activated dADP and persistent activity.
Figure 2: Patch-clamp recording from layer 5 pyramidal PFC neurons showing response to an ascending and descending input stimulus before and after mGluR activation.
Figure 3: The dAPD requires intracellular Ca2+ and can amplify and convert near-threshold inputs into sustained output only after an initial action potential.
Figure 4: Burst-induced dADP is mediated by mGluR5.
Figure 5: Dopamine reduces mGluR5- and burst-induced dADP through D1R-PKA pathway.
Figure 6: Repeated cocaine exposure reduces mGluR5- and burst-induced dADP and D1R modulation.
Figure 7: Repeated cocaine treatment reduces the mGluR5- and burst-mediated conversion of subthreshold input to suprathreshold action potential output and D1R modulation.

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Acknowledgements

We thank K. Huber (University of Texas Southwestern Medical Center at Dallas) for the mGluR1 and mGluR5 wild-type and knockout mice. This work was supported by National Institute on Drug Abuse grant R01-DA24040 (to D.C.C.), NIDA K award K-01DA017750 (to D.C.C.), a NARSAD Young Investigator award (to D.C.C.), National Institute on Drug Abuse institutional training grant T32-DA7290 (to M.A.F.), the Onassis Public Benefit Foundation (to K.S.), a Gulf War Syndrome contract from the US Department of Veterans Affairs and Veterans Affairs IDIQ contract VA549-P-0027 (awarded and administered by the Dallas, Texas, VA Medical Center). This paper is dedicated to the memory of Francis J. White, a close friend and mentor.

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K.S., F.-M.L., E.D.O. and D.C.C. conducted the patch-clamp experiments. K.S. and D.C.C. wrote the manuscript. M.A.F. performed behavioral experiments. C.P. carried out immunoblot experiments, and R.X. and M.X.Z. performed calcium imaging experiments in HEK cells. F.J.W. and D.C.C. supervised the project.

Corresponding author

Correspondence to Donald C Cooper.

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Sidiropoulou, K., Lu, FM., Fowler, M. et al. Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity. Nat Neurosci 12, 190–199 (2009). https://doi.org/10.1038/nn.2245

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