Motor impairment and adaptation in a novel non-human primate model of internal capsule infarct.

Loss of distal hand and finger control is among the most disabling consequences of stroke. Functional outcomes are typically worse when infarcts involve subcortical white matter tracts, particularly the internal capsule, yet most preclinical stroke models target cortical regions. To address this gap, we developed a non-human primate model of internal capsule infarct using stereotactically guided endothelin-1 injections to disrupt descending fibers from the primary motor cortex hand area.

Loss of intracellular FGF14 (iFGF14) increases excitability of mature hippocampal pyramidal neurons.

Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder associated with deficits in motor coordination and cognitive function. Mice lacking iFGF14 (Fgf14-/-) display similar phenotypes, and we have previously shown that the deficits in motor coordination reflect reduced excitability of cerebellar Purkinje neurons, owing to a hyperpolarizing shift in the voltage-dependence of voltage-gated Na+ (Nav) current steady-state inactivation. Here, we present the results of experiments designed to test the hypothesis that loss of iFGF14 also attenuates the intrinsic excitability of mature hippocampal pyramidal neurons.

Loss of Intracellular Fibroblast Growth Factor 14 (iFGF14) the Excitability of Mature Hippocampal and Cortical Pyramidal Neurons.

Mutations in , which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder associated with progressive deficits in motor coordination and cognitive function. Mice ( ) lacking iFGF14 display similar phenotypes, and we have previously shown that the deficits in motor coordination reflect excitability of cerebellar Purkinje neurons, owing to the loss of iFGF14-mediated regulation of the voltage-dependence of inactivation of the fast transient component of the voltage-gated Na (Nav) current, I . Here, we present the results of experiments designed to test the hypothesis that loss of iFGF14 also attenuates the intrinsic excitability of mature hippocampal and cortical pyramidal neurons.

Kv12-encoded K+ channels drive the day-night switch in the repetitive firing rates of SCN neurons.

Considerable evidence suggests that day-night rhythms in the functional expression of subthreshold potassium (K+) channels regulate daily oscillations in the spontaneous firing rates of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals. The K+ conductance(s) driving these daily rhythms in the repetitive firing rates of SCN neurons, however, have not been identified. To test the hypothesis that subthreshold Kv12.

Effects of NALCN-Encoded Na Leak Currents on the Repetitive Firing Properties of SCN Neurons Depend on K-Driven Rhythmic Changes in Input Resistance.

Neurons in the suprachiasmatic nucleus (SCN) generate circadian changes in the rates of spontaneous action potential firing that regulate and synchronize daily rhythms in physiology and behavior. Considerable evidence suggests that daily rhythms in the repetitive firing rates (higher during the day than at night) of SCN neurons are mediated by changes in subthreshold potassium (K) conductance(s). An alternative "bicycle" model for circadian regulation of membrane excitability in clock neurons, however, suggests that an increase in NALCN-encoded sodium (Na) leak conductance underlies daytime increases in firing rates.

Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors.

Voltage-gated sodium (NaV) channels are responsible for the initiation and propagation of action potentials. In the heart, the predominant NaV1.5 α subunit is composed of four homologous repeats (I-IV) and forms a macromolecular complex with multiple accessory proteins, including intracellular fibroblast growth factors (iFGF).

Kv12-Encoded K Channels Drive the Day-Night Switch in the Repetitive Firing Rates of SCN Neurons.

Considerable evidence suggests that day-night rhythms in the functional expression of subthreshold potassium (K ) channels regulate daily oscillations in the rates of spontaneous action potential firing of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals. The K conductance(s) driving these daily rhythms in repetitive firing rates, however, have not been identified. To test the hypothesis that subthreshold Kv12.

The Study of Security Priming on Avoidant Attentional Biases: Combining Microsaccadic Eye-Movement Measurement With a Dot-Probe Task.

Microsaccades are small fixational eye movements that have shown to index covert attentional shifts. The present experiment combined microsaccades with performance measures from a dot-probe task to study influences of attachment security priming on the attentional biases of individuals high in attachment avoidance. Security priming is an experimental manipulation aimed at boosting felt security.

Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits.

Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, NaV1.5, expressed in the mammalian heart.

Regional differences in the expression of tetrodotoxin-sensitive inward Ca and outward Cs/K currents in mouse and human ventricles.

Tetrodotoxin (TTX) sensitive inward Ca currents, I, have been identified in cardiac myocytes from several species, although it is unclear if I is expressed in all cardiac cell types, and if I reflects Ca entry through the main, Nav1.5-encoded, cardiac Na (Nav) channels. To address these questions, recordings were obtained with 2 mm Ca and 0 mm Na in the bath and 120 mm Cs in the pipettes from myocytes isolated from adult mouse interventricular septum (IVS), left ventricular (LV) endocardium, apex, and epicardium and from human LV endocardium and epicardium.

Endoplasmic Reticulum Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding and Redox-Sensitive Cardiac Fibroblast Activation.

Rationale: Cardiac fibrosis plays a critical role in the pathogenesis of heart failure. Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited, and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics.

Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior.

Rapidly activating and inactivating A-type K currents (I) encoded by Kv4.2 and Kv4.3 pore-forming (α) subunits of the Kv4 subfamily are key regulators of neuronal excitability.

Early remodeling of repolarizing K currents in the αMHC mouse model of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM), linked to mutations in myosin, myosin-binding proteins and other sarcolemmal proteins, is associated with increased risk of life threatening ventricular arrhythmias, and a number of animal models have been developed to facilitate analysis of disease progression and mechanisms. In the experiments here, we use the αMHC mouse line in which one αMHC allele harbors a common HCM mutation (in βMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male αMHC mice, well in advance of the onset of measurable left ventricular hypertrophy.

Stabilization of Kv4 protein by the accessory K(+) channel interacting protein 2 (KChIP2) subunit is required for the generation of native myocardial fast transient outward K(+) currents.

The fast transient outward K(+) current (Ito,f) underlies the early phase of myocardial action potential repolarization, contributing importantly to the coordinated propagation of activity in the heart and to the generation of normal cardiac rhythms. Native Ito,f channels reflect the tetrameric assembly of Kv4 pore-forming (α) subunits, and previous studies suggest roles for accessory and regulatory proteins in controlling the cell surface expression and the biophysical properties of Kv4-encoded Ito,f channels. Here, we demonstrate that the targeted deletion of the cytosolic accessory subunit, K(+) channel interacting protein 2 (KChIP2), results in the complete loss of the Kv4.

Differential expression of I(A) channel subunits Kv4.2 and Kv4.3 in mouse visual cortical neurons and synapses.

In cortical neurons, pore-forming alpha-subunits of the Kv4 subfamily underlie the fast transient outward K+ current (I(A)). Considerable evidence has accumulated demonstrating specific roles for I(A) channels in the generation of individual action potentials and in the regulation of repetitive firing. Although I(A) channels are thought to play a role in synaptic processing, little is known about the cell type- and synapse-specific distribution of these channels in cortical circuits.

KChIP2 modulates the cell surface expression of Kv 1.5-encoded K(+) channels.

The Kv channel interacting proteins (KChIPs) were identified in a yeast two hybrid screen using the N terminus of Kv4.3 as bait. Previous studies have demonstrated that KChIP2 associates with voltage-gated K(+) (Kv) pore-forming (alpha) subunits of the Kv4 subfamily and contributes to the formation of the rapidly inactivating and recovering Kv4-encoded cardiac transient outward K(+) channels, I(to,f).