Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex

Cai, Wei; Liu, Shu-Su; Li, Baoming; Zhang, Xue-Han

doi:10.1242/bio.058840

Cited by 12 publications

(7 citation statements)

References 64 publications

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“…In cerebellum, HCN channels enhance both the frequency and amplitude of spontaneous IPSCs (Southan et al, 2000). In contrast to the above findings that HCN channels promote inhibitory transmitter release, HCN channels decrease mIPSC frequency in globus pallidus (Boyes et al, 2007) and reduce the frequency of both mIPSCs and sIPSCs in medial prefrontal cortex (Cai et al, 2022). An inhibitory effect of HCN channels has also been reported in subsets of excitatory synaptic terminals in entorhinal cortex (Huang et al, 2009;Shah et al, 2004).…”

Section: Discussionmentioning

confidence: 92%

The HCN1 hyperpolarization-activated cyclic nucleotide-gated channel enhances evoked GABA release from parvalbumin positive interneurons

Bock

Buss

Lofaro

et al. 2022

Preprint

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Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the cationic Ihcurrent in neurons and regulate the excitability of neuronal networks. The function of HCN channels depends, in part, on their subcellular localization. Of the four HCN isoforms (HCN1-4), HCN1 is strongly expressed in the dendrites of pyramidal neurons in hippocampal area CA1 but also in presynaptic terminals of parvalbumin-positive interneurons (PV+ INs), which provide strong inhibitory control over hippocampal activity. Yet, little is known about how HCN1 channels in these cells regulate the evoked release of the inhibitory transmitter GABA from their axon terminals. Here, we used several genetic, optogenetic, electrophysiological and imaging techniques to investigate how the electrophysiological properties of PV+ INs are regulated by HCN1, including how HCN1 activity at presynaptic terminals regulates the release of GABA onto pyramidal neurons (PNs) in CA1. We found that application of HCN1 pharmacological blockers reduced the amplitude of the inhibitory postsynaptic potential recorded from CA1 pyramidal neurons in response to selective optogenetic stimulation of PV+ INs. Homozygous HCN1-/-knockout mice also show reduced IPSCs in postsynaptic cells. Finally, two-photon imaging using genetically encoded fluorescent calcium indicators revealed that HCN1 blockers reduced the probability that an extracellular electrical stimulating pulse evoked a Ca2+response in individual PV+ IN presynaptic boutons. Taken together, our results show that HCN1 channels in the axon terminals of PV+ interneurons facilitate GABAergic transmission in the hippocampal CA1 region.

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Section: Discussionmentioning

confidence: 92%

The HCN1 hyperpolarization-activated cyclic nucleotide-gated channel enhances evoked GABA release from parvalbumin positive interneurons

Bock

Buss

Lofaro

et al. 2022

Preprint

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“…TRIP8b regulates trafficking of HCN channels [105] and mainly associates with the AP-2 complex [106]. Moreover, while AP-2 and clathrin are not cell-type specific, both HCN1 and TRIP8b were found to be enriched at PV synapses [107], with HCN channels being specific to PV neurons and important for their high firing frequencies [108,109]. Given the link of PV-neurons with schizophrenia [110–114], these observations suggest that AP-2 and clathrin may be involved in a PV-neuron specific disruption of HCN channel trafficking with schizophrenia.…”

Section: Resultsmentioning

confidence: 99%

An atlas of protein-protein associations of human tissues prioritizes candidate disease genes

Laman Trip,

van Oostrum,

Memon

et al. 2024

Preprint

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Proteins that interact together participate in the same cellular process and influence the same organismal traits. Despite the progress in mapping protein-protein interactions we lack knowledge of how they differ between tissues. Due to coordinated (post)transcriptional control, protein complex members have highly correlated abundances that are predictive of functional association. Here, we have compiled 7873 proteomic samples measuring protein levels in 11 human tissues and use these to define an atlas with tissue-specific protein associations. This method recapitulates known protein complexes and the larger structural organization of the cell. Interactions of stable protein complexes are well preserved across tissues, while signaling and metabolic interactions show larger variation. Further, we find that less than 18% of differences between tissues are estimated to be due to differences in gene expression while cell-type specific cellular structures, such as synaptic components, represent a significant driver of differences between tissues. We further supported the brain protein association network through co-fractionation experiments in synaptosomes, curation of brain derived pull-down data and AlphaFold2 models. Together these results illustrate how this brain specific protein interaction network can functionally prioritize candidate genes within loci linked to brain disorders.

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“…Thus, depending on the given feeding contexts, the electrophysiological properties of HCN in sGRNs lead to playing dual roles with opposing effects in regulating bGRNs. The stabilization of membrane potential by HCNs was reported to decrease the spontaneous activity of neurons, as evidenced by miniature postsynaptic currents suppressed by presynaptic HCNs 44 . In this regard, the lower SP observed in the Ih f03355 labellar bristles than that of WT, even on the nonsweet sorbitol food (Fig.5B), may be attributed to the more facile fluctuations in resting membrane potential which could regulate the consumption of SP (further discussion below).…”

Section: Discussionmentioning

confidence: 99%

DrosophilaHCN mediates gustatory homeostasis by preserving sensillar transepithelial potential in sweet environments

Lee,

Park,

Joo

et al. 2024

Preprint

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Establishing transepithelial ion disparities is crucial for sensory functions in animals. In insect sensory organs called sensilla, a transepithelial potential, known as the sensillum potential (SP), arises through active ion transport across accessory cells, sensitizing receptor neurons such as mechanoreceptors and chemoreceptors. Because multiple receptor neurons are often co-housed in a sensillum and share SP, niche-prevalent overstimulation of single sensory neurons can compromise neighboring receptors by depleting SP. However, how such potential depletion is prevented to maintain sensory homeostasis remains unknown. Here, we find that theIh-encoded hyperpolarization-activated cyclic nucleotide gated (HCN) channel bolsters the activity of bitter-sensing gustatory receptor neurons (bGRNs), albeit acting in sweet-sensing GRNs (sGRNs). For this task, HCN maintains SP despite prolonged sGRN stimulation induced by the diet mimicking their sweet feeding niche, such as overripe fruit. We present evidence thatIh-dependent demarcation of sGRN excitability is implemented to throttle SP consumption, which may have facilitated adaptation to a sweetness-dominated environment. Thus, HCN expressed in sGRNs serves as a key component of a simple yet versatile peripheral coding that regulates bitterness for optimal food intake in two contrasting ways: sweet-resilient preservation of bitter aversion and the previously reported sweet-dependent suppression of bitter taste.

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Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex

Cited by 12 publications

References 64 publications

The HCN1 hyperpolarization-activated cyclic nucleotide-gated channel enhances evoked GABA release from parvalbumin positive interneurons

The HCN1 hyperpolarization-activated cyclic nucleotide-gated channel enhances evoked GABA release from parvalbumin positive interneurons

An atlas of protein-protein associations of human tissues prioritizes candidate disease genes

DrosophilaHCN mediates gustatory homeostasis by preserving sensillar transepithelial potential in sweet environments

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