Hippocampal cAMP regulates HCN channel function on two time scales with differential effects on animal behavior

Lyman, Kyle A.; Han, Ye; Zhou, Chengwen; Renteria, Isabelle; Besing, Gai-Linn K; Kurz, Jonathan E.; Chetkovich, Dane M.

doi:10.1126/scitranslmed.abl4580

Cited by 10 publications

(31 citation statements)

References 97 publications

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“…Knockdown (8,13) or knockout (KO) (15) of hippocampal HCN channels has been associated with an increase in antidepressant-like behavior (behavior that is similar to that of an animal given an antidepressant such as fluoxetine (16)). Moreover, we recently reported an increase in HCN channel expression in the postmortem hippocampi of human patients with MDD, which is consistent with findings from animal models of chronic stress (8,17,18). Although, these results suggest that directly targeting HCN channels with a small molecule antagonist could be an effective antidepressant strategy, HCN channels are also expressed in cardiac tissue where they play an essential role in pacemaking (19,20).…”

supporting

confidence: 87%

Discovery of a small-molecule inhibitor of the TRIP8b–HCN interaction with efficacy in neurons

Han

Iyamu

Clutter

et al. 2022

Journal of Biological Chemistry

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supporting

confidence: 87%

Discovery of a small-molecule inhibitor of the TRIP8b–HCN interaction with efficacy in neurons

Han

Iyamu

Clutter

et al. 2022

Journal of Biological Chemistry

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“…Nonetheless, given the relevance of the dHPC to spatial memory, it is possible that the observed female-specific increase in PKA-mediated signaling may contribute to ketamine’s effects within this cognitive domain in a sex-dependent manner. Activation of PKA signaling by ketamine mediated via elevated cAMP levels is known to impact cognitive processes 67 , and spatial memory is affected by elevated dHPC cAMP levels in a biphasic manner 17 . More specifically, Lyman and colleagues (2021) recently demonstrated that acute increases in dCA1 pyramidal neurons in chronically-stressed male and female mice impaired object location memory, and blunted response to the antidepressant citalopram in this behavioral task 17 .…”

Section: Resultsmentioning

confidence: 99%

“…Activation of PKA signaling by ketamine mediated via elevated cAMP levels is known to impact cognitive processes 67 , and spatial memory is affected by elevated dHPC cAMP levels in a biphasic manner 17 . More specifically, Lyman and colleagues (2021) recently demonstrated that acute increases in dCA1 pyramidal neurons in chronically-stressed male and female mice impaired object location memory, and blunted response to the antidepressant citalopram in this behavioral task 17 . Conversely, chronically-elevated dHPC cAMP levels improved performance in the same object location memory task.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, hippocampus-dependent memory impairment has been identified as one of the most significant measures of cognitive dysfunction observed in depressed patients when examined across several domains 16 . Animal models of chronic stress also produce impairments in spatial memory mediated by the dorsal hippocampus (dHPC) in mice 17 . Given observations of reduced hippocampal volume in patients with mood disorders 18 , 19 , spatial memory may be of particular interest as a target for antidepressant treatment 15 .…”

Section: Introductionmentioning

confidence: 99%

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Sex- and estrous-cycle dependent dorsal hippocampal phosphoproteomic changes induced by low-dose ketamine

Saland

Wilczak

Voss

et al. 2022

Sci Rep

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Numerous emotional and cognitive processes mediated by the hippocampus present differences between sexes and can be markedly influenced by hormonal status in males and females of several species. In rodents, the dorsal hippocampus (dHPC) is known to contribute to the rapid antidepressant actions of the NMDA receptor antagonist ketamine. We and others have demonstrated a greater sensitivity to the fast-acting antidepressant ketamine in female versus male rats that is estrogen- and progesterone-dependent. However, the underlying mechanisms remain unclear. Using an acute low dose (2.5 mg/kg) of ketamine that is behaviorally effective in female but not male rats, a label-free phosphoproteomics approach was employed to identify ketamine-induced changes in signaling pathway activation and phosphoprotein abundance within the dHPC of intact adult male rats and female rats in either diestrus or proestrus. At baseline, males and females showed striking dissimilarities in the dHPC proteome and phosphoproteome related to synaptic signaling and mitochondrial function—differences also strongly influenced by cycle stage in female rats. Notably, phosphoproteins enriched in PKA signaling emerged as being both significantly sex-dependent at baseline and also the primary target of ketamine-induced protein phosphorylation selectively in female rats, regardless of cycle stage. Reduced phosphoprotein abundance within this pathway was observed in males, suggesting bi-directional effects of low-dose ketamine between sexes. These findings present biological sex and hormonal milieu as critical modulators of ketamine’s rapid actions within this brain region and provide greater insight into potential translational and post-translational processes underlying sex- and hormone-dependent modulation of ketamine’s therapeutic effects.

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“…At the behavioural level, TRIP8b expression in CA1 neurons has been linked to major depressive disorder (MDD) and human MDD patients and animal models of chronic stress exhibit higher expression of hippocampal HCN1 ( Han et al, 2017 ; Kim et al, 2018 ; Lyman et al, 2021 ). Similarly, while acute cAMP upregulation can reduce spatial memory and motivated behaviours, chronically-elevated cAMP can increase motivated behaviours, possibly through down-regulation of TRIP8b ( Lyman et al, 2021 ). And TRIP8b knockout in mice contributes to increases in motivated behaviours, including more time spent mobile in forced swim and tail suspension tests ( Lewis et al, 2011 ; Han et al, 2017 ).…”

Section: Trip8bmentioning

confidence: 99%

Regulation of HCN Channels by Protein Interactions

et al. 2022

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Hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels are key regulators of subthreshold membrane potentials in excitable cells. The four mammalian HCN channel isoforms, HCN1-HCN4, are expressed throughout the body, where they contribute to diverse physiological processes including cardiac pacemaking, sleep-wakefulness cycles, memory, and somatic sensation. While all HCN channel isoforms produce currents when expressed by themselves, an emerging list of interacting proteins shape HCN channel excitability to influence the physiologically relevant output. The best studied of these regulatory proteins is the auxiliary subunit, TRIP8b, which binds to multiple sites in the C-terminus of the HCN channels to regulate expression and disrupt cAMP binding to fine-tune neuronal HCN channel excitability. Less is known about the mechanisms of action of other HCN channel interaction partners like filamin A, Src tyrosine kinase, and MinK-related peptides, which have a range of effects on HCN channel gating and expression. More recently, the inositol trisphosphate receptor-associated cGMP-kinase substrates IRAG1 and LRMP (also known as IRAG2), were discovered as specific regulators of the HCN4 isoform. This review summarizes the known protein interaction partners of HCN channels and their mechanisms of action and identifies gaps in our knowledge.

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Hippocampal cAMP regulates HCN channel function on two time scales with differential effects on animal behavior

Abstract: cAMP-mediated effect on HCN channel surface trafficking and mouse behavior depends on activation time scale.

Cited by 10 publications

References 97 publications

Discovery of a small-molecule inhibitor of the TRIP8b–HCN interaction with efficacy in neurons

Discovery of a small-molecule inhibitor of the TRIP8b–HCN interaction with efficacy in neurons

Sex- and estrous-cycle dependent dorsal hippocampal phosphoproteomic changes induced by low-dose ketamine

Regulation of HCN Channels by Protein Interactions

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