Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility

Abstract

wordsMain Text: 4252 words Abstract Background: Imbalance in prefrontal cortical (PFC) pyramidal neuron excitation:inhibition is thought to underlie symptomologies shared across stress-related disorders and neuropsychiatric disease, including dysregulation of emotion and cognitive function. G protein-gated inwardly rectifying K + (GIRK/Kir3) channels mediate excitability of medial PFC pyramidal neurons, however the functional role of these channels in mPFC-dependent regulation of affect, cognition, and cortical dynamics is unknown. Methods:In mice harboring a 'floxed' version of the kcnj3 (Girk1) gene, we used a viral-cre approach to disrupt GIRK1-containing channel expression in pyramidal neurons within the prelimbic (PL) or infralimbic (IL) cortices. Additional studies used a novel model of chronic unpredictable stress (CUS) to determine the impact on PL GIRK-dependent signaling and cognitive function. Results:In males, loss of pyramidal GIRK-dependent signaling in the PL, but not IL, differentially impacted measures of affect and motivation, and impaired working memory and cognitive flexibility. CUS produced similar deficits in affect and cognition that paralleled a reduction in PL pyramidal GIRK-dependent signaling akin to viral approaches. Viral-and stress-induced behavioral deficits were rescued by systemic injection of a novel, GIRK1-selective agonist, ML-297. Unexpectedly, neither ablation of PL GIRK-dependent signaling or exposure to the CUS regimen impacted affect or cognition in female mice.Conclusions: GIRK-dependent signaling in male mice, but not females, is critical for maintaining optimal PL function and behavioral control. Disruption of this inhibition may underlie stress-related dysfunction of the PL and represent a therapeutic target for treating stress-induced deficits in affect regulation and impaired cognition that reduce quality of life.

Circadian desynchronization attenuates information throughput of prefrontal cortex pyramidal neurons in mice

“…Our data shows that ECD increases GIRK1/2 channel activity, and this tips the balance of inter-region communication. Together, this work is in agreement with previous studies demonstrating the relationship between GIRK channel function and cognitive flexibility, and demonstrates that altered GIRK1 channel activity may serve as a substrate for the deficits in cognitive flexibility observed in ECD mice 28,61,64 .…”

“…Our previous work showed that ECD impacts the PFC by reducing pyramidal cell dendritic arborizations and impairs cognitive flexibility 13 . Notably, G protein-gated inwardly rectifying K + (GIRK) channels throughout the PFC contribute to the regulation of cognitive flexibility 15,27,28 . To test if GIRK1 (Kir3.1) channel function contributes to decreased information throughput in ECD mice independent of time-ofday, we evoked action potentials before and after the bath application of the selective GIRK1 channel agonist ML297 (10 µM) 28,29 (Fig.…”

“…Here we demonstrate that the consequences of circadian disruption extend to the functional level, reducing information throughput of pyramidal neurons by increasing the threshold for action potential firing, which is critical for communication with other brain regions, such as the hippocampus and amygdala. GIRK channels play a demonstrated role in pyramidal neurons and interneurons throughout the infralimbic and prelimbic cortices 15,27,28,63 . Dynamic changes in GIRK channels underlie stress-induced deficits in cognitive flexibility, and decreased GIRK channel function can impair fear learning, likely through altered communication between the PFC and hippocampus 28,64 .…”

“…GIRK channels play a demonstrated role in pyramidal neurons and interneurons throughout the infralimbic and prelimbic cortices 15,27,28,63 . Dynamic changes in GIRK channels underlie stress-induced deficits in cognitive flexibility, and decreased GIRK channel function can impair fear learning, likely through altered communication between the PFC and hippocampus 28,64 . Our data shows that ECD increases GIRK1/2 channel activity, and this tips the balance of inter-region communication.…”

The Role of Parvalbumin Interneuron GIRK Signaling in the Regulation of Affect and Cognition in Male and Female Mice

“…Our recent work has shown that disruption of GIRK1 signaling in mPFC prelimbic pyramidal neurons impairs cognitive performance in an attentional set-shifting model of cognitive flexibility (Anderson et al, 2020 ). Given prior research highlighting a role for PVI activity in cognitive control, we next assessed whether GIRK1 signaling in PVI also influences cognitive control.…”