Norepinephrine Drives Persistent Activity in Prefrontal Cortex via Synergistic α1 and α2 Adrenoceptors

Zizhen Zhang,Philippe Séguéla,Sonia Jego,Steven Cordeiro Matos,Antoine Adamantidis

doi:10.1371/journal.pone.0066122

Abstract

Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

Highlights

The prefrontal cortex (PFC) plays a significant role in high order brain functions such as working memory [1,2,3], a process that refers to the ability to maintain relevant information in a temporary buffer to guide behaviour
We found that both exogenous NE and endogenous NE released from the locus coeruleus induce persistent firing in pyramidal neurons of the PFC
We report that the NE-evoked persistent responses are completely blocked by the a1 antagonist prazosin while the selective a1 agonist phenylephrine induces persistent firing

Summary

Introduction

The prefrontal cortex (PFC) plays a significant role in high order brain functions such as working memory [1,2,3], a process that refers to the ability to maintain relevant information in a temporary buffer to guide behaviour. Dysfunction of PFC neural networks occurs in many psychiatric disorders including attention deficit hyperactivity disorder and post-traumatic stress disorder (PTSD) which are associated with hypersensitivity to acute stress and deficits in working memory. Persistent firing which outlasts the original stimulus can be sustained via recurrent network excitation within microcircuits of layer 2/3 pyramidal neurons of the PFC or from afferent inputs of subcortical areas [3,10,11]. Despite the known impact of stress and imbalanced monoamine levels on PFC function, the mechanisms underlying the modulation of intrinsic persistent firing by norepinephrine (NE) have not been addressed

Methods

Results

Conclusion