Prefrontal cortex HCN1 channels enable intrinsic persistent neural firing and executive memory function

Sébastien J. Thuault, Gaël Malleret, Christine Constantinople, Russell Nicholls, Irene Chen, Judy Zhu, Andrey Panteleyev, Svetlana Vronskaya, Matthew F. Nolan, Randy Bruno, Steven A. Siegelbaum, Eric R. Kandel

Research output: Contribution to journalArticle

Abstract

In many cortical neurons, HCN1 channels are the major contributors to I h , the hyperpolarization-activated current, which regulates the intrinsic properties of neurons and shapes their integration of synaptic inputs, paces rhythmic activity, and regulates synaptic plasticity. Here, we examine the physiological role of I h in deep layer pyramidal neurons in mouse prefrontal cortex (PFC), focusing on persistent activity, a form of sustained firing thought to be important for the behavioral function of the PFC during working memory tasks. We find that HCN1 contributes to the intrinsic persistent firing that is induced by a brief depolarizing current stimulus in the presence of muscarinic agonists. Deletion of HCN1 or acute pharmacological blockade of I h decreases the fraction of neurons capable of generating persistent firing. The reduction in persistent firing is caused by the membrane hyperpolarization that results from the deletion of HCN1 or I h blockade, rather than a specific role of the hyperpolarization-activated current in generating persistent activity. In vivo recordings show that deletion of HCN1 has no effect on up states, periods of enhanced synaptic network activity. Parallel behavioral studies demonstrate that HCN1 contributes to the PFC-dependent resolution of proactive interference during working memory. These results thus provide genetic evidence demonstrating the importance of HCN1 to intrinsic persistent firing and the behavioral output of the PFC. The causal role of intrinsic persistent firing in PFC-mediated behavior remains an open question.

Original languageEnglish (US)
Pages (from-to)13583-13599
Number of pages17
JournalJournal of Neuroscience
Volume33
Issue number34
DOIs
StatePublished - Aug 27 2013

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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Executive Function
Prefrontal Cortex
Short-Term Memory
Neurons
Muscarinic Agonists
Neuronal Plasticity
Pyramidal Cells
Pharmacology
Membranes

ASJC Scopus subject areas

  • Neuroscience(all)

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Thuault, S. J., Malleret, G., Constantinople, C., Nicholls, R., Chen, I., Zhu, J., ... Kandel, E. R. (2013). Prefrontal cortex HCN1 channels enable intrinsic persistent neural firing and executive memory function. Journal of Neuroscience, 33(34), 13583-13599. https://doi.org/10.1523/JNEUROSCI.2427-12.2013

Prefrontal cortex HCN1 channels enable intrinsic persistent neural firing and executive memory function. / Thuault, Sébastien J.; Malleret, Gaël; Constantinople, Christine; Nicholls, Russell; Chen, Irene; Zhu, Judy; Panteleyev, Andrey; Vronskaya, Svetlana; Nolan, Matthew F.; Bruno, Randy; Siegelbaum, Steven A.; Kandel, Eric R.

In: Journal of Neuroscience, Vol. 33, No. 34, 27.08.2013, p. 13583-13599.

Research output: Contribution to journalArticle

Thuault, SJ, Malleret, G, Constantinople, C, Nicholls, R, Chen, I, Zhu, J, Panteleyev, A, Vronskaya, S, Nolan, MF, Bruno, R, Siegelbaum, SA & Kandel, ER 2013, 'Prefrontal cortex HCN1 channels enable intrinsic persistent neural firing and executive memory function', Journal of Neuroscience, vol. 33, no. 34, pp. 13583-13599. https://doi.org/10.1523/JNEUROSCI.2427-12.2013
Thuault, Sébastien J. ; Malleret, Gaël ; Constantinople, Christine ; Nicholls, Russell ; Chen, Irene ; Zhu, Judy ; Panteleyev, Andrey ; Vronskaya, Svetlana ; Nolan, Matthew F. ; Bruno, Randy ; Siegelbaum, Steven A. ; Kandel, Eric R. / Prefrontal cortex HCN1 channels enable intrinsic persistent neural firing and executive memory function. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 34. pp. 13583-13599.
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