Sharp wave ripples (SPW-Rs) represent the most synchronous population pattern in the mammalian brain. Their excitatory output affects a wide area of the cortex and several subcortical nuclei. SPW-Rs occur during "off-line" states of the brain, associated with consummatory behaviors and non-REM sleep, and are influenced by numerous neurotransmitters and neuromodulators. They arise from the excitatory recurrent system of the CA3 region and the SPW-induced excitation brings about a fast network oscillation (ripple) in CA1. The spike content of SPW-Rs is temporally and spatially coordinated by a consortium of interneurons to replay fragments of waking neuronal sequences in a compressed format. SPW-Rs assist in transferring this compressed hippocampal representation to distributed circuits to support memory consolidation; selective disruption of SPW-Rs interferes with memory. Recently acquired and pre-existing information are combined during SPW-R replay to influence decisions, plan actions and, potentially, allow for creative thoughts. In addition to the widely studied contribution to memory, SPW-Rs may also affect endocrine function via activation of hypothalamic circuits. Alteration of the physiological mechanisms supporting SPW-Rs leads to their pathological conversion, "p-ripples," which are a marker of epileptogenic tissue and can be observed in rodent models of schizophrenia and Alzheimer's Disease. Mechanisms for SPW-R genesis and function are discussed in this review.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/hipo.22488

Hippocampal sharp wave‐ripple: A cognitive biomarker for episodic memory and planning

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family com...

Hyperpolarization-activated cation channels: from genes to function.

Most synaptic inputs are made onto the dendritic tree. Recent work has shown that dendrites play an active role in transforming synaptic input into neuronal output and in defining the relationships between active synapses. In this review, we discuss how these dendritic properties influence the rules governing the induction of synaptic plasticity. We argue that the location of synapses in the dendritic tree, and the type of dendritic excitability associated with each synapse, play decisive roles in determining the plastic properties of that synapse. Furthermore, since the electrical properties of the dendritic tree are not static, but can be altered by neuromodulators and by synaptic activity itself, we discuss how learning rules may be dynamically shaped by tuning dendritic function. We conclude by describing how this reciprocal relationship between plasticity of dendritic excitability and synaptic plasticity has changed our view of information processing and memory storage in neuronal networks.

Dendritic Excitability and Synaptic Plasticity

The majority of all febrile seizures represent a benign syndrome that does not require extensive testing or long term medication. A careful history of the febrile seizure, family history, developmental history and physical examination can identify those infants and children with this syndrome. While one-third of this group will experience additional febrile seizures, there is no significant increase in the incidence of later epilepsy or neurological sequelae. The parents of these children need to be reassured and educated about this syndrome. They should understand the emergency treatment of seizures and aggressively treat fever. The more difficult task for the physician is to correctly identify those children who experience nonbenign seizures. Careful history and physical examination can accurately identify this group. Further evaluation including neuroimaging, electroencephalogram and developmental assessment may be necessary. In those children with a high risk of later epilepsy, treatment with an antiepileptic drug should be considered.

Febrile seizures : recognition and management

Pacemaking is a basic physiological process, and the cellular mechanisms involved in this function have always attracted the keen attention of investigators The “funny” ( I f) current, originally described in sinoatrial node myocytes as an inward current activated on hyperpolarization to the diastolic range of voltages, has properties suitable for generating repetitive activity and for modulating spontaneous rate The degree of activation of the funny current determines, at the end of an action potential, the steepness of phase 4 depolarization; hence, the frequency of action potential firing Because I f is controlled by intracellular cAMP and is thus activated and inhibited by β-adrenergic and muscarinic M2 receptor stimulation, respectively, it represents a basic physiological mechanism mediating autonomic regulation of heart rate Given the complexity of the cellular processes involved in rhythmic activity, an exact quantification of the extent to which I f and other mechanisms contribute to pacemaking is still a debated issue; nonetheless, a wealth of information collected since the current was first described more than 30 years ago clearly agrees to identify I f as a major player in both generation of spontaneous activity and rate control I f- dependent pacemaking has recently advanced from a basic, physiologically relevant concept, as originally described, to a practical concept that has several potentially useful clinical applications and can be valuable in therapeutically relevant conditions Typically, given their exclusive role in pacemaking, f-channels are ideal targets of drugs aiming to pharmacological control of cardiac rate Molecules able to bind specifically to and block f-channels can thus be used as pharmacological tools for heart rate reduction with little or no adverse cardiovascular side effects Indeed a selective f-channel inhibitor, ivabradine, is today commercially available as a tool in the treatment of stable chronic angina Also, several loss-of-function mutations of HCN4 (hyperpolarization-activated, cyclic-nucleotide gated 4), the major constitutive subunit of f-channels in pacemaker cells, are known today to cause rhythm disturbances, such as for example inherited sinus bradycardia Finally, gene- or cell-based methods for in situ delivery of f-channels to silent or defective cardiac muscle represent novel approaches for the development of biological pacemakers eventually able to replace electronic devices

This article is the introduction of a new thematic series on Mechanisms of Pacemaking in the Heart , which includes the following articles: Be Still, My Beating Heart – Never! [2010;106:238–239] Development of the Pacemaker Tissues of The Heart [2010;106:240–254] Mapping Cardiac Pacemaker Circuits: Methodological Puzzles of the Sinoatrial Node Optical Mapping [2010;106:255–271] The Role of The Funny Current in Pacemaker Activity Ca2+ Cycling in the Mechanism of Pacemaking Cardiac Pacemaking: Historical Overview and Future Directions Dennis Noble Guest Editor and Brian O'Rourke Editor

The Role of the Funny Current in Pacemaker Activity

SUMMARY Ion channel dysfunction or ‘‘channelopathy’’ is a proven cause of epilepsy in the relatively uncommon genetic epilepsies with Mendelian inheritance. But numerous examples of acquired channelopathy in experimental animal models of epilepsy following brain injury have also been demonstrated. Our understanding of channelopathy has grown due to advances in electrophysiology techniques that have allowed the study of ion channels in the dendrites of pyramidal neurons in cortex and hippocampus. The apical dendrites of pyramidal neurons comprise the vast majority of neuronal surface membrane area, and thus the majority of the neuronal ion channel population. Investigation of dendritic ion channels has demonstrated remarkable plasticity in ion channel localization and biophysical properties in epilepsy, many of which produce hyperexcitability and may contribute to the development and maintenance of the epileptic state. Herein we review recent advances in dendritic physiology and cell biology, and their relevance to epilepsy.

/pdf/dendritic-ion-channelopathy-in-acquired-epilepsy-4qpeutr9mv.pdf

Dendritic ion channelopathy in acquired epilepsy

Epilepsy is associated with loss of expression and function of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels. Previously, we showed that loss of HCN channel-mediated current ( I h ) occurred in the dendrites of CA1 hippocampal pyramidal neurons after pilocarpine-induced status epilepticus (SE), accompanied by loss of HCN1 channel protein expression. However, the precise onset and mechanistic basis of HCN1 channel loss post-SE was unclear, particularly whether it preceded the onset of spontaneous recurrent seizures and could contribute to epileptogenesis or development of the epileptic state. Here, we found that loss of I h and HCN1 channel expression began within an hour after SE and involved sequential processes of dendritic HCN1 channel internalization, delayed loss of protein expression, and later downregulation of mRNA expression. We also found that an in vitro SE model reproduced the rapid loss of dendritic I h , demonstrating that this phenomenon was not specific to in vivo SE. Together, these results show that HCN1 channelopathy begins rapidly and persists after SE, involves both transcriptional and nontranscriptional mechanisms, and may be an early contributor to epileptogenesis.

https://www.jneurosci.org/content/jneuro/31/40/14291.full.pdf

Rapid Loss of Dendritic HCN Channel Expression in Hippocampal Pyramidal Neurons following Status Epilepticus

Subcortical band heterotopia (SBH) is seen predominantly in females, resulting from mutations in the X-linked doublecortin (DCX) gene, and can present with mild mental retardation and epilepsy. Males carrying DCX mutations usually demonstrate lissencephaly and are clinically much more severely affected. This article reports two cases of males with SBH indistinguishable from the female phenotype, both resulting from somatic mosaicism for DCX mutation.

Males with epilepsy, complete subcortical band heterotopia, and somatic mosaicism for DCX

Key points

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, particularly that of the HCN1 isoform, are enriched in the distal dendrites of hippocampal CA1 pyramidal neurons; these channels have physiological functions with respect to decreasing neuronal excitability. 


In the present study, we aimed to investigate phosphorylation as a mechanism controlling Ih amplitude and HCN1 surface expression in hippocampal principal neurons under normal physiological conditions. 


Tyrosine phosphorylation decreased Ih amplitude at maximal activation (maximal Ih), without altering HCN1 surface expression, in two classes of hippocampal principal neurons. Inhibition of serine/threonine protein phosphatases 1 and 2A decreased maximal Ih and HCN1 surface expression in hippocampal principal neurons. 


Protein kinase C (PKC) activation irreversibly diminished Ih and HCN1 surface expression, whereas PKC inhibition augmented Ih and HCN1 surface expression. PKC activation increased HCN1 channel phosphorylation. 


These results demonstrate the novel finding of a phosphorylation mechanism, dependent on PKC activity, which bidirectionally modulates Ih amplitude and HCN1channel surface expression in hippocampal principal neurons under normal physiological conditions. 




Abstract
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels attenuate excitability in hippocampal pyramidal neurons. Loss of HCN channel-mediated current (Ih), particularly that mediated by the HCN1 isoform, occurs with the development of epilepsy. Previously, we showed that, following pilocarpine-induced status epilepticus, there are two independent changes in HCN function in dendrites: decreased Ih amplitude associated with a loss of HCN1 surface expression and a hyperpolarizing shift in voltage-dependence of activation (gating). The hyperpolarizing shift in gating was attributed to decreased phosphorylation as a result of a loss of p38 mitogen-activated protein kinase activity and increased calcineurin activity; however, the mechanisms controlling Ih amplitude and HCN1 surface expression under epileptic or normal physiological conditions are poorly understood. We aimed to investigate phosphorylation as a mechanism regulating Ih amplitude and HCN1 surface expression (i.e. as is the case for HCN gating) in hippocampal principal neurons under normal physiological conditions. We discovered that inhibition of either tyrosine phosphatases or the serine/threonine protein phosphatases 1 and 2A decreased Ih at maximal activation in hippocampal CA1 pyramidal dendrites and pyramidal-like principal neuron somata from naive rats. Furthermore, we found that inhibition of PP1/PP2A decreased HCN1 surface expression, whereas tyrosine phosphatase inhibition did not. Protein kinase C (PKC) activation reduced Ih amplitude and HCN1 surface expression, whereas PKC inhibition produced the opposite effect. Inhibition of protein phosphatases 1 and 2A and activation of PKC increased the serine phosphorylation state of the HCN1 protein. The effect of PKC activation on Ih was irreversible. These results indicate that PKC bidirectionally modulates Ih amplitude and HCN1 surface expression in hippocampal principal neurons.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP270453

Protein kinase C bidirectionally modulates Ih and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel surface expression in hippocampal pyramidal neurons.

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) voltage-gated ion channels are widely expressed in cortex, hippocampus, and thalamus, brain regions that underlie the generation of both focal and generalized-onset seizures. Greater understanding of the contribution of HCN channel function to neuronal physiology has been paralleled by increasing evidence for their role in epilepsy. Genetic deletion of the HCN2 channel subtype leads to an absence epilepsy phenotype, while deletion of the HCN1 subtype produces hypersensitivity to provoked seizures and accelerates epileptogenesis. Pharmacological blockade of HCN channels likewise produces neuronal hyperexcitability, while one or more antiepileptic drugs appear to upregulate HCN channel function. In animal models of acquired epilepsy, loss of HCN channel expression and function occurs during the earliest phases of epileptogenesis, and promotes the occurrence of seizures. Thus, numerous lines of evidence point to a role for HCN channels in epilepsy, especially in acquired syndromes. In this chapter, I describe how the biophysical properties of HCN channels position them to play a significant role in epileptogenesis; how emerging evidence suggests the existence of HCN channelopathy in human epilepsy; and how the mechanisms underlying HCN channelopathy could be targeted in antiepileptic therapies.

Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Ion Channelopathy in Epilepsy

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