The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.

/pdf/glutamate-receptor-ion-channels-structure-regulation-and-148yts0p6h.pdf

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

http://chialvo.org/Curso/UBACurso/DIA9/Papers/reviewBrainNets1.pdf

Exploring the brain network: A review on resting-state fMRI functional connectivity

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.

SeminarAmyotrophic lateral sclerosis

https://www.normalesup.org/~vorgogoz/articles/D.pachea-references/alternative-splicing/Stamm2005-alternative-splicing-review.pdf

Function of alternative splicing.

Background: Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS); however, a comprehensive examination of complement expression in this disease has not been performed. This study therefore aimed to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5 and CD88) and regulators (CD55 and CD59a) in the lumbar spinal cord of hSOD1 G93A mice during defined disease stages. Methods: hSOD1 G93A and wild-type mice were examined at four different ages of disease progression. mRNA and protein expression of complement components and regulators were examined using quantitative PCR, western blotting and ELISA. Localisation of complement components within lumbar spinal cord was investigated using immunohistochemistry. Statistical differences between hSOD1 G93A and wild-type mice were analysed using a two-tailed t-test at each stage of disease progression. Results: We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1 G93A mice. CD88 was also increased during disease progression, with immunolocalisation demonstrating expression on motor neurons and increasing expression on microglia surrounding the regions of motor neuron death. Conclusions: These results indicate that local complement activation and increased expression of CD88 may contribute to motor neuron death and ALS pathology in the hSOD1 G93A mouse. Hence, reducing complement-induced

of amyotrophic lateral sclerosis

ALSFRS-R score and its ratio: a useful predictor for ALS-progression.

Changes of resting state brain networks in amyotrophic lateral sclerosis.

Objective

To detect mutations in GABRA1 in idiopathic generalized epilepsy.



Methods

GABRA1 was sequenced in 98 unrelated idiopathic generalized epilepsy patients. Patch clamping and confocal imaging was performed in transfected mammalian cells.



Results

We identified the first GABRA1 mutation in a patient with childhood absence epilepsy. Functional studies showed no detectable GABA-evoked currents for the mutant, truncated receptor, which was not integrated into the surface membrane.



Interpretation

We conclude that this de novo mutation can contribute to the cause of “sporadic” childhood absence epilepsy by a loss of function and haploinsufficiency of the GABAA receptor α1-subunit, and that GABRA1 mutations rarely are associated with idiopathic generalized epilepsy. Ann Neurol 2006;59:983–987

A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy.

Oxidative stress and inflammation are important pathogenetic mechanisms in amyotrophic lateral sclerosis (ALS). Nuclear erythroid 2-related factor 2 (Nrf2) is a basic region leucine-zipper transcription factor that binds to the antioxidant response element, thereby regulating the expression of many genes that are involved in cellular antioxidant and anti-inflammatory defense. Under normal conditions, Nrf2 activation is inhibited by Kelch-like ECH-associated protein 1 (Keap1). We investigated the potential involvement of the Nrf2/antioxidant response element signaling pathway in the selective degeneration of motor neurons in ALS. Nrf2 and Keap1 expression was analyzed in primary motor cortex and spinal cord postmortem tissue samples from ALS patients and controls by in situ hybridization histochemistry, quantitative real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In ALS samples, there was a reduction of Nrf2 mRNA and protein expression in neurons, whereas Keap1 mRNA expression was increased in the motor cortex. These results suggest that alterations in this signaling cascade occur in motor neurons in ALS and that they may contribute to chronic motor neuron degeneration.

Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis.

Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic t

Klaus Krampfl

Papers

ALSFRS-R score and its ratio: a useful predictor for ALS-progression.

Changes of resting state brain networks in amyotrophic lateral sclerosis.

A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy.

Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis.

The Nonpsychotropic Cannabinoid Cannabidiol Modulates and Directly Activates Alpha-1 and Alpha-1-Beta Glycine Receptor Function