Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes.

Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (I) were recently identified in mature OLG and shown to play a role in regulating myelin length.

Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice.

Tonic current through hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels is influencing neuronal firing properties and channel function is strongly influenced by the brain-specific auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Since Kv1.2 channels and TRIP8b were also suggested to interact, we assessed brain Kv1.

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

Major depressive disorder is a critical public health problem with a lifetime prevalence of nearly 17% in the United States. One potential therapeutic target is the interaction between hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and an auxiliary subunit of the channel named tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). HCN channels regulate neuronal excitability in the mammalian hippocampus, and recent work has established that antagonizing HCN function rescues cognitive impairment caused by chronic stress.

Modulation of pacemaker channel function in a model of thalamocortical hyperexcitability by demyelination and cytokines.

A consensus is yet to be reached regarding the exact prevalence of epileptic seizures or epilepsy in multiple sclerosis (MS). In addition, the underlying pathophysiological basis of the reciprocal interaction among neuroinflammation, demyelination, and epilepsy remains unclear. Therefore, a better understanding of cellular and network mechanisms linking these pathologies is needed.

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

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels regulate neuronal excitability and represent a possible therapeutic target for major depressive disorder (MDD). These channels are regulated by intracellular cyclic adenosine monophosphate (cAMP). However, the relationship between cAMP signaling and the influence of HCN channels on behavior remains opaque.

Variability in sub-threshold signaling linked to Alzheimer's disease emerges with age and amyloid plaque deposition in mouse ventral CA1 pyramidal neurons.

The hippocampus is vulnerable to deterioration in Alzheimer's disease (AD). It is, however, a heterogeneous structure, which may contribute to the differential volumetric changes along its septotemporal axis during AD progression. Here, we investigated amyloid plaque deposition along the dorsoventral axis in two strains of transgenic AD (ADTg) mouse models.

Enhanced Synaptic Transmission in the Extended Amygdala and Altered Excitability in an Extended Amygdala to Brainstem Circuit in a Dravet Syndrome Mouse Model.

Dravet syndrome (DS) is a developmental and epileptic encephalopathy with an increased incidence of sudden death. Evidence of interictal breathing deficits in DS suggests that alterations in subcortical projections to brainstem nuclei may exist, which might be driving comorbidities in DS. The aim of this study was to determine whether a subcortical structure, the bed nucleus of the stria terminalis (BNST) in the extended amygdala, is activated by seizures, exhibits changes in excitability, and expresses any alterations in neurons projecting to a brainstem nucleus associated with respiration, stress response, and homeostasis.

Characterization of the HCN Interaction Partner TRIP8b/PEX5R in the Intracardiac Nervous System of TRIP8b-Deficient and Wild-Type Mice.

The tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b/PEX5R) is an interaction partner and auxiliary subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are key for rhythm generation in the brain and in the heart. Since TRIP8b is expressed in central neurons but not in cardiomyocytes, the TRIP8b-HCN interaction has been studied intensely in the brain, but is deemed irrelevant in the cardiac conduction system. Still, to date, TRIP8b has not been studied in the intrinsic cardiac nervous system (ICNS), a neuronal network located within epicardial fat pads.

Cognitive aging is associated with redistribution of synaptic weights in the hippocampus.

Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive.

The structure and function of TRIP8b, an auxiliary subunit of hyperpolarization-activated cyclic-nucleotide gated channels.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed throughout the mammalian central nervous system (CNS). These channels have been implicated in a wide range of diseases, including Major Depressive Disorder and multiple subtypes of epilepsy. The diversity of functions that HCN channels perform is in part attributable to differences in their subcellular localization.

Entorhinal velocity signals reflect environmental geometry.

The entorhinal cortex contains neurons that represent self-location, including grid cells that fire in periodic locations and velocity signals that encode running speed and head direction. Although the size and shape of the environment influence grid patterns, whether entorhinal velocity signals are equally influenced or provide a universal metric for self-motion across environments remains unknown. Here we report that speed cells rescale after changes to the size and shape of the environment.

Moving Metabolism to Make Inroads in a Model of Mitochondrial Epilepsy.

[Box: see text].

Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function.

Temporal lobe epilepsy (TLE) is a prevalent neurological disorder with many patients experiencing poor seizure control with existing anti-epileptic drugs. Thus, novel insights into the mechanisms of epileptogenesis and identification of new drug targets can be transformative. Changes in ion channel function have been shown to play a role in generating the aberrant neuronal activity observed in TLE.

Oligodendrocyte K4.1 Channels Clear Out Congested K.

[Box: see text].

Current Opinions and Consensus for Studying Tremor in Animal Models.

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied.

CRAFTing a New Approach to Antiepileptic Drug Discovery.

Srivastava PK, van Eyll J, Godard P, Mazzuferi M, Delahaye-Duriez A, Steenwinckel JV, et al. A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target. Nat Commun.

PUMILIO1 Links Epilepsy to Spinocerebellar Ataxia.

A Mild PUM1 Mutation Is Associated With Adult-Onset Ataxia, Whereas Haploinsufficiency Causes Developmental Delay and Seizures Gennarino VA, Palmer EE, McDonell LM, et al. Cell. 2018;172(5):924-936.

Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice.

β-Site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) is the β-secretase enzyme that initiates production of the toxic amyloid-β peptide that accumulates in the brains of patients with Alzheimer's disease (AD). Hence, BACE1 is a prime therapeutic target, and several BACE1 inhibitor drugs are currently being tested in clinical trials for AD. However, the safety of BACE1 inhibition is unclear.

HCN channels in the hippocampus regulate active coping behavior.

Active coping is an adaptive stress response that improves outcomes in medical and neuropsychiatric diseases. To date, most research into coping style has focused on neurotransmitter activity and little is known about the intrinsic excitability of neurons in the associated brain regions that facilitate coping. Previous studies have shown that HCN channels regulate neuronal excitability in pyramidal cells and that HCN channel current (I ) in the CA1 area increases with chronic mild stress.

Publisher Correction: Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive.

In the version of this article originally published, a URL provided in the Methods section was incorrect. The URL had a solidus at the end but should have appeared as http://www.nature.

Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.

Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons.

Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive.

Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice.

Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice.

Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are important regulators of excitability in neural, cardiac, and other pacemaking cells, which are often altered in disease. In mice, loss of HCN2 leads to cardiac dysrhythmias, persistent spike-wave discharges similar to those seen in absence epilepsy, ataxia, tremor, reduced neuropathic and inflammatory pain, antidepressant-like behavior, infertility, and severely restricted growth. While many of these phenotypes have tissue-specific mechanisms, the cause of restricted growth in HCN2 knockout animals remains unknown.