Role of KCNQ potassium channels in stress-induced deficit of working memory

Abstract

The prefrontal cortex (PFC) mediates higher cognition but is impaired by stress exposure when high levels of catecholamines activate calcium-cAMP-protein kinase A (PKA) signaling. The current study examined whether stress and increased cAMP-PKA signaling in rat medial PFC (mPFC) reduce pyramidal cell firing and impair working memory by activating KCNQ potassium channels. KCNQ2 channels were found in mPFC layers II/III and V pyramidal cells, and patch-clamp recordings demonstrated KCNQ currents that were increased by forskolin or by chronic stress exposure, and which were associated with reduced neuronal firing. Low dose of KCNQ blockers infused into rat mPFC improved cognitive performance and prevented acute pharmacological stress-induced deficits. Systemic administration of low doses of KCNQ blocker also improved performance in young and aged rats, but higher doses impaired performance and occasionally induced seizures. Taken together, these data demonstrate that KCNQ channels have powerful influences on mPFC neuronal firing and cognitive function, contributing to stress-induced PFC dysfunction.

Prefrontal inhibition of neuronal Kv7 channels enhances prepulse inhibition of acoustic startle reflex and resistance to hypofrontality

“…In this study, we tested the hypothesis that enhancing prefrontal excitability by inhibition of neuronal K v 7 channel activity may alleviate glutamatergic hypofrontality that has been linked to the pathogenesis of neuropsychiatric disorders such as schizophrenia (Arnsten et al, 2019; Arnsten, Paspalas, Gamo, Yang, & Wang, 2010). Using the PPI assay, we examined the effect of genetic suppression and pharmacological inhibition of neuronal K v 7 channels on the acoustic startle response, a response that is deficient in patients with schizophrenia (Mena et al, 2016) or schizophrenia‐like models (Takahashi & Kamio, 2018).…”

A dopamine gradient controls access to distributed working memory in monkey cortex

“…In addition, dopamine increased the strength of transmission via NMDA receptors (Seamans et al 2001a). On the other hand, high stimulation of D1 receptors resulted increased adaptation in excitatory cells (potentially an M-current, via KCNQ potassium channels, Arnsten et al 2019), mimicking the net inhibitory effect of high concentrations of D1-agonists.…”

“…High levels of D1 agonism lead to a reduction in pyramidal cell firing, particularly during the delay period of working memory tasks. D1 receptor stimulation may lead to inhibition of ongoing activity by engaging an intracellular pathway involving cyclic AMP, protein kinase A and either HCN or KCNQ channels (Arnsten et al 2019;Gamo et al 2015;Vijayraghavan et al 2007). The mechanisms by which HCN channels may hyperpolarise the cell are still under debate (George et al 2009;Pereira 2014).…”

Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species

“…However, under conditions of uncontrollable stress, there are high levels of NE and DA release in the PFC ( Finlay et al, 1995 , Murphy et al, 1996 ), which engage α1-AR and D1R to drive Ca 2+ -PKC and cAMP-PKA signaling, rapidly opening nearby K + channels to weaken PFC network connectivity and impair working memory and top-down control ( Fig. 4 B); ( Arnsten et al, 2019 , Birnbaum et al, 2004 , Gamo et al, 2015 ). Thus, feedforward Ca 2+ -PKC-cAMP-PKA-K + signaling can very quickly take PFC “offline”.…”

“…5 B) and in the spine neck. Later studies showed that KCNQ2 channels, which are opened by PKA signaling, are also localized on spines near the synapse and the spine apparatus ( Arnsten et al, 2019 ). Thus, the constellation of signaling molecules needed to dynamically alter network strength are all concentrated in layer III dlPFC dendritic spines, supporting the model proposed in Fig.…”