KCC2 reverse mode helps to clear postsynaptically released potassium at glutamatergic synapses.

Extracellular potassium [K] elevation during synaptic activity retrogradely modifies presynaptic release and astrocytic uptake of glutamate. Hence, local K clearance and replenishment mechanisms are crucial regulators of glutamatergic transmission and plasticity. Based on recordings of astrocytic inward rectifier potassium current I and K-sensitive electrodes as sensors of [K] as well as on in silico modeling, we demonstrate that the neuronal K-Cl co-transporter KCC2 clears local perisynaptic [K] during synaptic excitation by operating in an activity-dependent reversed mode.

Interferon-γ augments GABA release in the developing neocortex nitric oxide synthase/soluble guanylate cyclase and constrains network activity.

Interferon-γ (IFN-γ), a cytokine with neuromodulatory properties, has been shown to enhance inhibitory transmission. Because early inhibitory neurotransmission sculpts functional neuronal circuits, its developmental alteration may have grave consequences. Here, we investigated the acute effects of IFN-γ on γ-amino-butyric acid (GABA)ergic currents in layer 5 pyramidal neurons of the somatosensory cortex of rats at the end of the first postnatal week, a period of GABA-dependent cortical maturation.

Interferon-γ enhances neocortical synaptic inhibition by promoting membrane association and phosphorylation of GABA receptors in a protein kinase C-dependent manner.

Interferon-γ (IFN-γ), an important mediator of the antiviral immune response, can also act as a neuromodulator. CNS IFN-γ levels rise acutely in response to infection and therapeutically applied IFN-γ provokes CNS related side effects. Moreover, IFN-γ plays a key role in neurophysiological processes and a variety of chronic neurological and neuropsychiatric conditions.

Non-thermal effects of radiofrequency electromagnetic fields.

We explored the non-thermal effects of radiofrequency (RF) electromagnetic fields and established a theoretical framework to elucidate their electrophysiological mechanisms. In experiments, we used a preclinical treatment device to treat the human colon cancer cell lines HT-29 and SW480 with either water bath heating (WB-HT) or 13.56 MHz RF hyperthermia (RF-HT) at 42 °C for 60 min and analyzed the proliferation and clonogenicity.

Interferon-γ acutely augments inhibition of neocortical layer 5 pyramidal neurons.

Background: Interferon-γ (IFN-γ, a type II IFN) is present in the central nervous system (CNS) under various conditions. Evidence is emerging that, in addition to its immunological role, IFN-γ modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-β (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons.

Altered inhibition and excitation in neocortical circuits in congenital microcephaly.

Congenital microcephaly is highly associated with intellectual disability. Features of autosomal recessive primary microcephaly subtype 3 (MCPH3) also include hyperactivity and seizures. The disease is caused by biallelic mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2.

The anticonvulsant lamotrigine enhances I in layer 2/3 neocortical pyramidal neurons of patients with pharmacoresistant epilepsy.

Alterations of the hyperpolarization activated nonselective cation current (I) are associated with epileptogenesis. Accordingly, the second-generation antiepileptic drug lamotrigine (LTG) enhances I in rodent hippocampus. We directly evaluated here whether LTG fails to enhance I in neocortical slices from patients with pharmacoresistant epilepsy.

Synaptic Phospholipid Signaling Modulates Axon Outgrowth via Glutamate-dependent Ca2+-mediated Molecular Pathways.

Altered synaptic bioactive lipid signaling has been recently shown to augment neuronal excitation in the hippocampus of adult animals by activation of presynaptic LPA2-receptors leading to increased presynaptic glutamate release. Here, we show that this results in higher postsynaptic Ca2+ levels and in premature onset of spontaneous neuronal activity in the developing entorhinal cortex. Interestingly, increased synchronized neuronal activity led to reduced axon growth velocity of entorhinal neurons which project via the perforant path to the hippocampus.

Use Dependent Attenuation of Rat HCN1-Mediated Ih in Intact HEK293 Cells.

Background/aims: Cationic currents (Ih) through the fast activating and relatively cAMP insensitive subtype of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, HCN1, are limited by cytosolic factors in mammalian cells. This cytosolic HCN1 break is boosted by changes in membrane voltage that are not characterized on a biophysical level, yet.

Methods: We overexpressed rat (r)HCN1 in human embryonic kidney cells (HEK293) and recorded pharmacologically isolated Ih in cell-attached or whole-cell mode of the patch-clamp technique.

Studying Axonal Outgrowth and Regeneration of the Corticospinal Tract in Organotypic Slice Cultures.

Studies of axonal outgrowth and regeneration after spinal cord injury are hampered by the complexity of the events involved. Here, we present a simple and improved in vitro approach to investigate outgrowth, regeneration of the corticospinal tract, and intrinsic parenchymal responses. We prepared organotypic co-cultures using explants from the motor cortex of postnatal donor mice ubiquitously expressing green fluorescent protein and cervical spinal cord from wild type pups of the same age.

Protein kinase C activation mediates interferon-β-induced neuronal excitability changes in neocortical pyramidal neurons.

Background: Cytokines are key players in the interactions of the immune and nervous systems. Recently, we showed that such interplay is mediated by type I interferons (IFNs), which elevate the excitability of neocortical pyramidal neurons. A line of indirect evidence suggested that modulation of multiple ion channels underlies the effect.

Plasticity-related gene 5 promotes spine formation in murine hippocampal neurons.

The transmembrane protein plasticity-related genes 3 and 5 (PRG3 and PRG5) increase filopodial formation in various cell lines, independently of Cdc42. However, information on the effects of PRG5 during neuronal development is sparse. Here, we present several lines of evidence for the involvement of PRG5 in the genesis and stabilization of dendritic spines.

HCN1 subunits contribute to the kinetics of I(h) in neonatal cortical plate neurons.

The distribution of ion channels in neurons regulates neuronal activity and proper formation of neuronal networks during neuronal development. One of the channels is the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel constituting the molecular substrate of hyperpolarization-activated current (I(h)). Our previous study implied a role for the fastest activating subunit HCN1 in the generation of Ih in rat neonatal cortical plate neurons.

Protein kinase C activation inhibits rat and human hyperpolarization activated cyclic nucleotide gated channel (HCN)1--mediated current in mammalian cells.

Background/aims: Hyperpolarization activated cyclic nucleotide gated 1 (HCN1) channels determine neuronal excitability in several brain regions. In contrast to HCN2 and HCN4, HCN1 is less sensitive to cAMP and the number of other known modulators is limited. One of those, the protein kinase C (PKC), showed opposing effects on mouse HCN1 channels expressed in Xenopus oocytes.

Plasticity-related gene 3 promotes neurite shaft protrusion.

Background: Recently, we and others proposed plasticity-related gene 3 (PRG3) as a novel molecule in neuritogenesis based on PRG3 overexpression experiments in neuronal and non-neuronal cell lines. However, direct information on PRG3 effects in neuronal development and, in particular, its putative spatio-temporal distribution and conditions of action, is sparse.

Results: We demonstrate here that PRG3 induces filopodia formation in HEK293 cells depending on its N-glycosylation status.

Current views on regulation and function of plasticity-related genes (PRGs/LPPRs) in the brain.

Plasticity-related genes (PRGs, Lipid phosphate phosphatase-related proteins LPPRs) are a defined as a subclass of the lipid phosphate phosphatase (LPP) superfamily, comprising so far five brain- and vertebrate-specific membrane-spanning proteins. LPPs interfere with lipid phosphate signaling and are thereby involved in mediating the extracellular concentration and signal transduction of lipid phosphate esters such as lysophosphatidate (LPA) and spingosine-1 phosphate (S1P). LPPs dephosphorylate their substrates through extracellular catalytic domains, thus making them ecto-phosphatases.

Elevation in type I interferons inhibits HCN1 and slows cortical neuronal oscillations.

Central nervous system (CNS) inflammation involves the generation of inducible cytokines such as interferons (IFNs) and alterations in brain activity, yet the interplay of both is not well understood. Here, we show that in vivo elevation of IFNs by viral brain infection reduced hyperpolarization-activated currents (Ih) in cortical pyramidal neurons. In rodent brain slices directly exposed to type I IFNs, the hyperpolarization-activated cyclic nucleotide (HCN)-gated channel subunit HCN1 was specifically affected.

Distinct perinatal features of the hyperpolarization-activated non-selective cation current I(h) in the rat cortical plate.

Background: During neocortical development, multiple voltage- and ligand-gated ion channels are differentially expressed in neurons thereby shaping their intrinsic electrical properties. One of these voltage-gated ion channels, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and its current I(h), is an important regulator of neuronal excitability. Thus far, studies on an early I(h) appearance in rodent neocortex are missing or conflicting.

Optimizing a rodent model of Parkinson's disease for exploring the effects and mechanisms of deep brain stimulation.

Deep brain stimulation (DBS) has become a treatment for a growing number of neurological and psychiatric disorders, especially for therapy-refractory Parkinson's disease (PD). However, not all of the symptoms of PD are sufficiently improved in all patients, and side effects may occur. Further progress depends on a deeper insight into the mechanisms of action of DBS in the context of disturbed brain circuits.

I(h) "run-up" in rat neocortical neurons and transiently rat or human HCN1-expressing HEK293 cells.

Hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN) are key determinants of CNS functions. Here we describe an increase in hyperpolarization-activated current (I(h)) at the beginning of whole-cell recordings in rat layer 5 cortical neurons. For a closer investigation of this I(h) increase, we overexpressed the predominant layer 5 rat subunit HCN1 in HEK293 cells.

Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling.

Plasticity related gene-1 (PRG-1) is a brain-specific membrane protein related to lipid phosphate phosphatases, which acts in the hippocampus specifically at the excitatory synapse terminating on glutamatergic neurons. Deletion of prg-1 in mice leads to epileptic seizures and augmentation of EPSCs, but not IPSCs. In utero electroporation of PRG-1 into deficient animals revealed that PRG-1 modulates excitation at the synaptic junction.

Interferon-beta modulates protein synthesis in the central nervous system.

Interferon-beta (IFN-beta), acting canonically via the modulation of transcription, affects neocortical pyramidal neurons. By use of 2-D differential gel electrophoresis and subsequent mass spectrometry we identified IFN-beta regulated proteins in the central nervous system. These proteins are involved in cytoskeleton assembly, protein transport and nucleotide metabolism and, as such, serve regenerative and protective functions.

Differential astroglial activation in 6-hydroxydopamine models of Parkinson's disease.

In rat models of Parkinson's disease, injections of 6-hydroxydopamine (6-OHDA) into different areas of the basal ganglia result in dopaminergic neurodegeneration in the substantia nigra. The extent and time course of the dopaminergic lesions varies between the models. While the effects on neurons have been extensively studied, little is known about the effects on astrocytes.

Specific properties of sodium currents in multipotent striatal progenitor cells.

This study investigates the impact of intrinsic currents on early neural development. A rat striatal ST14A cell line immortalized by SV40 large T antigen was employed as a model system because these cells act as multipotent neural progenitors when maintained at a permissive temperature of 33 degrees C. The whole-cell patch-clamp, molecular and immunocytochemical experiments point to a unique role of sodium currents in the multipotential stage of neural development.