Early developmental alterations of CA1 pyramidal cells in Dravet syndrome.

Dravet Syndrome (DS) is most often caused by heterozygous loss-of-function mutations in the voltage-gated sodium channel gene SCN1A (Na1.1), resulting in severe epilepsy and neurodevelopmental impairment thought to be cause by reduced interneuron excitability. However, recent studies in mouse models suggest that interneuron dysfunction alone does not completely explain all the cellular and network impairments seen in DS.

On-demand cell-autonomous gene therapy for brain circuit disorders.

Several neurodevelopmental and neuropsychiatric disorders are characterized by intermittent episodes of pathological activity. Although genetic therapies offer the ability to modulate neuronal excitability, a limiting factor is that they do not discriminate between neurons involved in circuit pathologies and "healthy" surrounding or intermingled neurons. We describe a gene therapy strategy that down-regulates the excitability of overactive neurons in closed loop, which we tested in models of epilepsy.

Extracellular GABA waves regulate coincidence detection in excitatory circuits.

Key Points: Rapid changes in neuronal network activity trigger widespread waves of extracellular GABA in hippocampal neuropil. Elevations of extracellular GABA narrow the coincidence detection window for excitatory inputs to CA1 pyramidal cells. GABA transporters control the effect of extracellular GABA on coincidence detection.

Pro-inflammatory Cytokines Drive Deregulation of Potassium Channel Expression in Primary Synovial Fibroblasts.

Unlabelled: The synovium secretes synovial fluid, but is also richly innervated with nociceptors and acts as a gateway between avascular joint tissues and the circulatory system. Resident fibroblast-like synoviocytes' (FLS) calcium-activated potassium channels ( ) change in activity in arthritis models and this correlates with FLS .

Objective: To investigate this activation in an model of inflammatory arthritis; 72 h treatment with cytokines TNFα and IL1β.

Inorganic Polyphosphate Regulates AMPA and NMDA Receptors and Protects Against Glutamate Excitotoxicity via Activation of P2Y Receptors.

Glutamate is one of the most important neurotransmitters in the process of signal transduction in the CNS. Excessive amounts of this neurotransmitter lead to glutamate excitotoxicity, which is accountable for neuronal death in acute neurological disorders, including stroke and trauma, and in neurodegenerative diseases. Inorganic polyphosphate (PolyP) plays multiple roles in the mammalian brain, including function as a calcium-dependent gliotransmitter mediating communication between astrocytes, while its role in the regulation of neuronal activity is unknown.

The Functional Role of Spontaneously Opening GABA Receptors in Neural Transmission.

Ionotropic type of γ-aminobutyric acid receptors (GABARs) produce two forms of inhibitory signaling: phasic inhibition generated by rapid efflux of neurotransmitter GABA into the synaptic cleft with subsequent binding to GABARs, and tonic inhibition generated by persistent activation of extrasynaptic and/or perisynaptic GABARs by GABA continuously present in the extracellular space. It is widely accepted that phasic and tonic GABAergic inhibition is mediated by receptor groups of distinct subunit composition and modulated by different cytoplasmic mechanisms. Recently, however, it has been demonstrated that spontaneously opening GABARs (s-GABARs), which do not need GABA binding to enter an active state, make a significant input into tonic inhibitory signaling.

Glutamate Receptor Probing with Rapid Application and Solution Exchange (RASE).

Probing of glutamate receptors at sub-millisecond time scale is a key element needed for understanding of their response kinetics, neural signal transduction, and, in a wider context, intercellular cross talk. One of the classical techniques used to obtain this type of data in electrophysiology is placing a recording pipette in front of a double-barrel solution application pipette, which provides a rapid switch between two solutions. Here we describe a modification of this classical technique, which utilizes a solution application pipette with several loading capillaries.

Biphasic Modulation of NMDA Receptor Function by Metabotropic Glutamate Receptors.

A recently reported rapid potentiation of NMDA receptors by Group I metabotropic glutamate receptors (mGluRIs) via a Homer protein link is distinct from the classical, relatively slow inhibitory G-protein-associated signaling triggered by mGluRI activation. The relationship between these two mechanisms remains unknown. Here, we focused on the mGluRI-dependent modulation of NMDAR response in hippocampal dentate gyrus granule cells and cerebellar granule cells of C57BL6-J mice and found that these two contrasting mechanisms overlap competitively on the time scale from hundreds of milliseconds to seconds, with the net effect depending on the cell type.

Feature Article: Selective modulation of tonically active GABA receptor functional subgroups by G-proteins and protein kinase C.

Here we study intracellular mechanisms which regulate inhibitory signaling delivered through continuously (tonically) open ionotropic receptors of γ-aminobutyric acid (GABA) of dentate gyrus granule cells (DGCs). We found that, apart of classical GABA-A receptors (GABARs) which can be activated by GABA binding, a significant part of tonic inhibitory current is delivered by newly discovered spontaneously opening GABARs (s-GABARs), which enter active state without binding of GABA. We have also found that conventional GABARs and s-GABARs are regulated by different intracellular mechanisms, which may overlap and thus induce various signaling repercussions.

Spontaneously opening GABA receptors play a significant role in neuronal signal filtering and integration.

Continuous (tonic) charge transfer through ionotropic receptors of γ-aminobutyric acid (GABARs) is an important mechanism of inhibitory signalling in the brain. The conventional view has been that tonic GABA-ergic inhibitory currents are mediated by low concentrations of ambient GABA. Recently, however, it was shown that the GABA-independent, spontaneously opening GABARs (s-GABARs), may contribute significantly to the tonic GABAR current.

Novel mechanism of modulation at a ligand-gated ion channel; action of 5-Cl-indole at the 5-HT A receptor.

Background And Purpose: The 5-HT receptor is a prototypical member of the Cys-loop ligand-gated ion channel (LGIC) superfamily and an established therapeutic target. In addition to activation via the orthosteric site, receptor function can be modulated by allosteric ligands. We have investigated the pharmacological action of Cl-indole upon the 5-HT A receptor and identified that this positive allosteric modulator possesses a novel mechanism of action for LGICs.