Novel Q234K variant, identified in patients with long QT syndrome and epileptiform activity, induces both gain- and loss-of-function of slowly activating delayed rectifier potassium currents.

Introduction: KCNQ1 and KCNE1 form slowly activating delayed rectifier potassium currents (I). Loss-of-function of I by variants causes type-1 long QT syndrome (LQTS). Also, some variants are reported to cause epilepsy.

Hippocampus-related cognitive disorders develop in the absence of epilepsy and ataxia in the heterozygous mutant mice .

-associated epilepsy and ataxia frequently accompany cognitive impairments as devastating co-morbidities. However, it is unclear whether the cognitive deficits are consequences secondary to the neurological symptoms elicited by mutations. To address this issue, mutant mice (), and in particular /+ heterozygotes, serve as a suitable model system, given that /+ heterozygotes fail to display spontaneous absence epilepsy and ataxia typically observed in / homozygotes.

L-bupivacaine Inhibition of Nociceptive Transmission in Rat Peripheral and Dorsal Horn Neurons.

Background: Although the widely used single L-enantiomers of local anesthetics have less toxic effects on the cardiovascular and central nervous systems, the mechanisms mediating their antinociceptive actions are not well understood. The authors hypothesized that significant differences in the ion channel blocking abilities of the enantiomers of bupivacaine would be identified.

Methods: The authors performed electrophysiologic analysis on rat dorsal root ganglion neurons in vitro and on spinal transmissions in vivo.

A computational analysis of the effect of sevoflurane in a human ventricular cell model of long QT syndrome: Importance of repolarization reserve in the QT-prolonging effect of sevoflurane.

The slowly and rapidly activating delayed rectifier K channels (I and I, respectively) contribute to the repolarization of ventricular action potential in human heart and thereby determine QT interval on an electrocardiogram. Loss-of-function mutations in genes encoding I and I cause type 1 and type 2 long QT syndrome (LQT1 and LQT2, respectively), accompanied by a high risk of malignant ventricular arrhythmias and sudden cardiac death. This study was designed to investigate which cardiac electrophysiological conditions exaggerate QT-prolonging and arrhythmogenic effects of sevoflurane.

Differential Involvement of Kinase Activity of Ca/Calmodulin-Dependent Protein Kinase IIα in Hippocampus- and Amygdala-Dependent Memory Revealed by Kinase-Dead Knock-In Mouse.

Ca/calmodulin-dependent protein kinase IIα (CaMKIIα) is a key mediator of activity-dependent neuronal modifications and has been implicated in the molecular mechanisms of learning and memory. Indeed, several types of CaMKIIα knock-in (KI) and knock-out (KO) mice revealed impairments in hippocampal synaptic plasticity and behavioral learning. On the other hand, a similar role for CaMKIIα has been implicated in amygdala-dependent memory, but detailed analyses have not much been performed yet.

Characterization of Nociceptive Behaviors Induced by Formalin in the Glabrous and Hairy Skin of Rats.

Introduction: Glabrous skin and hairy skin are innervated by different types of noxious fibers. However, the different nociceptive behaviors induced by formalin, a commonly used model of acute inflammatory pain, have not yet been systematically examined in the glabrous and hairy skin.

Methods: In this study, we compared nociceptive behaviors induced by formalin injections (2%, 4%, and 8%) into either glabrous skin (plantar surface) of the hind paw or hairy skin of the hind limb in adult rats.

Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.

Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A.

Synaptic Multivesicular Release in the Cerebellar Cortex: Its Mechanism and Role in Neural Encoding and Processing.

The number of synaptic vesicles released during fast release plays a major role in determining the strength of postsynaptic response. However, it remains unresolved how the number of vesicles released in response to action potentials is controlled at a single synapse. Recent findings suggest that the Cav2.

Inhibitory synaptic transmission from the substantia nigra pars reticulata to the ventral medial thalamus in mice.

The cortico-basal ganglia-thalamic loop circuit is involved in variety of motor, association and limbic functions. The basal ganglia receive neural information from various areas of the cerebral cortex and transfer them back to the frontal and motor cortex via the ventral medial (VM), and the anterior-ventral lateral thalamic complex. The projection from the basal ganglia to the thalamus is GABAergic, and, therefore, the output from the basal ganglia cannot directly evoke excitation in the thalamic nuclei.

Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy.

Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1, encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear.

Compromised maturation of GABAergic inhibition underlies abnormal network activity in the hippocampus of epileptic Ca2+ channel mutant mice, tottering.

Cholinergically induced network activity is a useful analogue of theta rhythms involved in memory processing or epileptiform activity in the hippocampus, providing a powerful tool to elucidate the mechanisms of synchrony in neuronal networks. In absence epilepsy, although its association with cognitive impairments has been reported, the mechanisms underlying hippocampal synchrony remain poorly investigated. Here we simultaneously recorded electrical activities from 64 sites in hippocampal slices of CaV2.

Cav2.1 channels control multivesicular release by relying on their distance from exocytotic Ca2+ sensors at rat cerebellar granule cells.

The concomitant release of multiple numbers of synaptic vesicles [multivesicular release (MVR)] in response to a single presynaptic action potential enhances the flexibility of synaptic transmission. However, the molecular mechanisms underlying MVR at a single CNS synapse remain unclear. Here, we show that the Cav2.

Large-scale somatotopic refinement via functional synapse elimination in the sensory thalamus of developing mice.

Functional synapse elimination and strengthening are crucial developmental processes in the formation of precise neuronal circuits in the somatosensory system, but the underlying alterations in topographical organization are not yet fully understood. To address this issue, we generated transgenic mice in which afferent fibers originating from the whisker-related brain region, called the maxillary principal trigeminal nucleus (PrV2), were selectively visualized with genetically expressed fluorescent protein. We found that functional synapse elimination drove and established large-scale somatotopic refinement even after the thalamic barreloid architecture was formed.

Systemic dexmedetomidine augments inhibitory synaptic transmission in the superficial dorsal horn through activation of descending noradrenergic control: an in vivo patch-clamp analysis of analgesic mechanisms.

α2-Adrenoceptors are widely distributed throughout the central nervous system (CNS) and the systemic administration of α2-agonists such as dexmedetomidine produces clinically useful, centrally mediated sedation and analgesia; however, these same actions also limit the utility of these agents (ie, unwanted sedative actions). Despite a wealth of data on cellular and synaptic actions of α2-agonists in vitro, it is not known which neuronal circuits are modulated in vivo to produce the analgesic effect. To address this issue, we made in vivo recordings of membrane currents and synaptic activities in superficial spinal dorsal horn neurons and examined their responses to systemic dexmedetomidine.

Enhanced inhibitory neurotransmission in the cerebellar cortex of Atp1a3-deficient heterozygous mice.

Dystonia is characterized by excessive involuntary and prolonged simultaneous contractions of both agonist and antagonist muscles. Although the basal ganglia have long been proposed as the primary region, recent studies indicated that the cerebellum also plays a key role in the expression of dystonia. One hereditary form of dystonia, rapid-onset dystonia with parkinsonism (RDP), is caused by loss of function mutations of the gene for the Na pump α3 subunit (ATP1A3).

Regulation of ERK1/2 mitogen-activated protein kinase by NMDA-receptor-induced seizure activity in cortical slices.

Extracellular signal-regulated kinase 1/2 (ERK1/2) that belongs to a subfamily of mitogen-activated protein kinases (MAPKs) plays diverse roles in the central nervous system. Activation of ERK1/2 has been observed in various types of neuronal excitation, including seizure activity in vivo and in vitro, as well as in NMDA-receptor (NMDA-R)-dependent long-term potentiation in the hippocampus. On the other hand, recent studies in cultured neurons have shown that NMDA-R stimulation could result in either ERK1/2 activation or non-activation, depending on the pharmacological manipulations.

Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Aβ generation in Alzheimer's disease.

Background: One of the best-characterized causative factors of Alzheimer's disease (AD) is the generation of amyloid-β peptide (Aβ). AD subjects are at high risk of epileptic seizures accompanied by aberrant neuronal excitability, which in itself enhances Aβ generation. However, the molecular linkage between epileptic seizures and Aβ generation in AD remains unclear.

The Role of HCN Channels on Membrane Excitability in the Nervous System.

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels were first reported in heart cells and are recently known to be involved in a variety of neural functions in healthy and diseased brains. HCN channels generate inward currents when the membrane potential is hyperpolarized. Voltage dependence of HCN channels is regulated by intracellular signaling cascades, which contain cyclic AMP, PIP(2), and TRIP8b.

Paired-pulse facilitation of multivesicular release and intersynaptic spillover of glutamate at rat cerebellar granule cell-interneurone synapses.

A simple form of presynaptic plasticity, paired-pulse facilitation (PPF), has been explained as a transient increase in the probability of vesicular release. Using the whole-cell patch-clamp technique to record synaptic activity in rat cerebellar slices, we found different forms of presynaptically originated short-term plasticity during glutamatergic excitatory neurotransmission from granule cells (GCs) to molecular-layer interneurones (INs). Paired-pulse activation of GC axons at short intervals (30-100 ms) elicited not only a facilitation in the peak amplitude (PPF(amp)), but also a prolongation in the decay-time constant (PPP(decay)) of the EPSCs recorded from INs.

Rewiring of afferent fibers in the somatosensory thalamus of mice caused by peripheral sensory nerve transection.

The remodeling of neural circuitry and changes in synaptic efficacy after peripheral sensory nerve injury are considered the basis for functional reorganization in the brain, including changes in receptive fields. However, when or how the remodeling occurs is largely unknown. Here we show the rapid rewiring of afferent fibers in the mature ventral posteromedial thalamic nucleus of mice after transection of the peripheral whisker sensory nerve, using the whole-cell voltage-clamp technique.

In vivo patch-clamp recording from locus coeruleus neurones in the rat brainstem.

Locus coeruleus (LC) neurones extend noradrenergic projections throughout the neuroaxis and are involved in homeostatic functions such as pain modulation, arousal and cardio-respiratory control. To address the cellular mechanisms underlying pain modulation we have developed a patch-clamp recording technique from LC neurones in anaesthetized rats. These recordings showed LC discharge in vivo to be driven by both spontaneous membrane potential oscillations and CNQX-sensitive EPSCs opposed by bicuculine-sensitive IPSCs.

Roles of the subthalamic nucleus and subthalamic HCN channels in absence seizures.

Absence seizures consist of a brief and sudden impairment of consciousness. They are characterized by bilaterally synchronized spike and wave discharges (SWDs), which reflect abnormal oscillations in the thalamocortical loops. Recent studies have suggested that the basal ganglia are involved in generation of the SWDs, but their roles are poorly understood at the molecular and cellular levels.

Differential regulation of Purkinje cell dendritic spines in rolling mouse Nagoya (tg/tg), P/Q type calcium channel (α1(A)/Ca(v)2.1) mutant.

Voltage dependent calcium channels (VDCC) participate in regulation of neuronal Ca(2+). The Rolling mouse Nagoya (Cacna1a(tg-rol)) is a spontaneous P/Q type VDCC mutant, which has been suggested as an animal model for some human neurological diseases such as autosomal dominant cerebellar ataxia (SCA6), familial hemiplegic migraine and episodic ataxia type-2. Morphology of Purkinje cell (PC) dendritic spine is suggested to be regulated by signal molecules such as Ca(2+) and by interactions with afferent inputs.

Synapse- and subtype-specific modulation of synaptic transmission by nicotinic acetylcholine receptors in the ventrobasal thalamus.

The rodent thalamic ventrobasal complex (VB) which is a subdivision of somatosensory thalamus receives two excitatory inputs through the medial lemniscal synapse, which is a sensory afferent synapse, and the corticothalamic synapse from layer VI of the somatosensory cortex. In addition, the VB also receives cholinergic inputs from the brain stem, and nicotinic acetylcholine receptors (nAChRs) are highly expressed in the VB. Little is known, however, how acetylcholine (ACh) modulates synaptic transmission at the medial lemniscal and corticothalamic synapses in the VB.