Expression of the pacemaker channel HCN4 in excitatory interneurons in the dorsal horn of the murine spinal cord

Nakagawa, Taku; Yasaka, Tetsuo; Nakashima, Noriyuki; Takeya, Mitsue; Oshita, Kensuke; Tsuda, Masayuki; Yamaura, Ken; Takano, Makoto

doi:10.1186/s13041-020-00666-6

Cited by 8 publications

(4 citation statements)

References 54 publications

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“…3H), consistent with the single cell transcriptomic data. We did not detect any Hcn4 mRNA in the spinal cord, which we attribute to technical difficulties as Hcn4 has previously been detected in rodent spinal cord (Tu et al, 2004;Hughes et al, 2012;Nakagawa et al, 2020).…”

Section: A N U S C R I P Tcontrasting

confidence: 47%

Electrophysiological Properties of Proprioception-Related Neurons in the Intermediate Thoracolumbar Spinal Cord

Espinosa,

Pop,

Lai

2024

eNeuro

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Proprioception, the sense of limb and body position, is required to produce accurate and precise movements. Proprioceptive sensory neurons transmit muscle length and tension information to the spinal cord. The function of excitatory neurons in the intermediate spinal cord, which receive this proprioceptive information, remains poorly understood. Using genetic labeling strategies and patch clamp techniques in acute spinal cord preparations in mice, we set out to uncover how two sets of spinal neurons, Clarke's column (CC) andAtoh1-lineage neurons, respond to electrical activity and how their inputs are organized. Both sets of neurons are located in close proximity in lamina V-VII of the thoracolumbar spinal cord and have been described to receive proprioceptive signals. We find that a majority of CC neurons have a tonic firing-type and express a distinctive hyperpolarization-activated current (Ih).Atoh1-lineage neurons, which cluster into two spatially distinct populations, are mostly a fading firing-type and display similar electrophysiological properties to each other, possibly due to their common developmental lineage. Finally, we find that CC neurons respond to stimulation of lumbar dorsal roots, consistent with prior knowledge that CC neurons receive hindlimb proprioceptive information. In contrast, using a combination of electrical stimulation, optogenetic stimulation, and transsynaptic rabies virus tracing, we found thatAtoh1-lineage neurons receive heterogeneous, predominantly local thoracic inputs that includeParvalbumin-lineage sensory afferents and local interneuron presynaptic inputs. Altogether, we find that CC andAtoh1-lineage neurons have distinct membrane properties and sensory input organization, representing different subcircuit modes of proprioceptive information processing.Significance StatementHow excitatory spinal cord neurons in the intermediate spinal cord integrate and relay proprioceptive sensory information is not well understood. Our investigation focuses on two sets of spinal neurons that receive proprioceptive information, but whose electrophysiological response properties have not been previously described. We characterize both their passive and active electrophysiological properties in addition to their input connectivity. We identify unique electrophysiological signatures of each population as well as features of their input organization. We find that a hyperpolarization-activated current distinguishes Clarke's column neurons and thatAtoh1-lineage neurons receive predominantly local inputs. These experiments lay the foundation for future endeavors aimed at understanding the mechanisms by which proprioceptive information is integrated and relayed through these neurons.

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Section: A N U S C R I P Tcontrasting

confidence: 47%

Electrophysiological Properties of Proprioception-Related Neurons in the Intermediate Thoracolumbar Spinal Cord

Espinosa,

Pop,

Lai

2024

eNeuro

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“…HCN4 encodes for the hyperpolarization-activated cyclic nucleotide-gated potassium channel 4. HCN4 channels are distributed in the neocortex (Battefeld et al, 2012 ), cerebellum (Zúñiga et al, 2016 ), hippocampus and spinal cord (Hughes et al, 2013 ; Nakagawa et al, 2020 ), cerebellar Purkinje fibers (Han et al, 2002 ), thalamus (Kanyshkova et al, 2012 ; Oyrer et al, 2019 ), corpus striatum, globus pallidus, and habenula (Oyrer et al, 2019 ). They can be found in neurons that regulate spontaneous rhythmic activity, such as in the thalamocortical relay, substantia nigra, cholinergic interneurons, and medial habenula (Santoro et al, 2000 ; Notomi and Shigemoto, 2004 ).…”

Section: Resultsmentioning

confidence: 99%

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Kessi

Peng

Duan

et al. 2022

Front. Mol. Neurosci.

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BackgroundHyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy.ObjectivesThis systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype–phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets.MethodsThe review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021.ResultsWe identified pathogenic variants of HCN1 (n = 24), HCN2 (n = 8), HCN3 (n = 2), and HCN4 (n = 6) that were associated with epilepsy in 74 cases (43 HCN1, 20 HCN2, 2 HCN3, and 9 HCN4). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising HCN1 (n = 4), HCN2 (n = 2), HCN3 (n = 2), and HCN4 (n = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults (n = 10) than children (n = 2). HCN1 variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as HCN2 variants p.S632W and delPPP (p.719–721), were associated with different phenotypes. HCN1 p.L157V and HCN4 p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers.ConclusionWe recommend clinicians to include HCN genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.

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“…We similarly find that the GABA1-3 clusters of macaques, which show the highest expression of the glycine transporter 2 ( SLC6A5 ), are also enriched in the deeper laminae (III-V). Similarly, the hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 , which has been implicated in mechanical allodynia (touch-evoked pain) under neuropathic conditions due to its presence on PKCγ neurons, is enriched in macaque clusters GLUT9 and GLUT10 which correspond to the mouse Prkcg family 50 .…”

Section: Discussionmentioning

confidence: 99%

Spatial, transcriptomic and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition

Arokiaraj

Kleyman

Chamessian

et al. 2022

Preprint

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SummaryThe spinal dorsal horn transforms incoming somatosensory information and transmits it supraspinally to generate modality-specific sensory percepts. The lack of an established framework for the molecular and cellular organization of the dorsal horn across species has greatly hampered delineating precisely how this region processes somatosensory information, including pain. Furthermore, the translation potential of the rodent work is unclear without data from higher order species. To fill these gaps, we performed single nucleus RNA-sequencing of Rhesus macaque dorsal horn and compared the results to a recently reported meta-analysis of mouse. Because dorsal horn laminae serve as a key organizing principle for function, we also determined the laminar location of each identified cell type. The work provides a comprehensive cross-species cellular and molecular database that will be critical for decoding the logic of dorsal horn somatosensory circuits and validating preclinical targets.

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Expression of the pacemaker channel HCN4 in excitatory interneurons in the dorsal horn of the murine spinal cord

Cited by 8 publications

References 54 publications

Electrophysiological Properties of Proprioception-Related Neurons in the Intermediate Thoracolumbar Spinal Cord

Electrophysiological Properties of Proprioception-Related Neurons in the Intermediate Thoracolumbar Spinal Cord

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Spatial, transcriptomic and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition

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