New insight into the molecular etiopathogenesis of konzo: Cyanate could be a plausible neurotoxin contributing to konzo, contrary to thiocyanate.

Introduction: Chronic cassava-derived cyanide poisoning is associated with the appearance of konzo, a tropical spastic paraparesis due to selective upper motor neuron damage. Whether the disease is caused by a direct action of cyanide or its metabolites is still an open question. This preliminary study assessed the neurotoxic effects of thiocyanate (SCN) and cyanate (OCN), two cyanide metabolites hypothesized to be plausible toxic agents in konzo.

Differential regulation of glycinergic and GABAergic nanocolumns at mixed inhibitory synapses.

Super-resolution imaging has revealed that key synaptic proteins are dynamically organized within sub-synaptic domains (SSDs). To examine how different inhibitory receptors are regulated, we carried out dual-color direct stochastic optical reconstruction microscopy (dSTORM) of GlyRs and GABA Rs at mixed inhibitory synapses in spinal cord neurons. We show that endogenous GlyRs and GABA Rs as well as their common scaffold protein gephyrin form SSDs that align with pre-synaptic RIM1/2, thus creating trans-synaptic nanocolumns.

Embryonic macrophages and microglia ablation alter the development of dorsal root ganglion sensory neurons in mouse embryos.

Microglia are known to regulate several aspects of the development of the central nervous system. When microglia colonize the spinal cord, from E11.5 in the mouse embryo, they interact with growing central axons of dorsal root ganglion sensory neurons (SNs), which suggests that they may have some functions in SN development.

Persistent Sodium Current Drives Excitability of Immature Renshaw Cells in Early Embryonic Spinal Networks.

Spontaneous network activity (SNA) emerges in the spinal cord (SC) before the formation of peripheral sensory inputs and central descending inputs. SNA is characterized by recurrent giant depolarizing potentials (GDPs). Because GDPs in motoneurons (MNs) are mainly evoked by prolonged release of GABA, they likely necessitate sustained firing of interneurons.

Axoglial synapses are formed onto pioneer oligodendrocyte precursor cells at the onset of spinal cord gliogenesis.

Virtually all oligodendrocyte precursors cells (OPCs) receive glutamatergic and/or GABAergic synapses that are lost upon their differentiation into oligodendrocytes in the postnatal and adult brain. Although OPCs are generated at mid-embryonic stages, several weeks before the onset of myelination, it remains unknown when and where OPCs receive their first synapses and become susceptible to the influence of neuronal activity. In the embryonic spinal cord, neuro-epithelial precursors in the pMN domain cease generating cholinergic motor neurons (MNs) to produce OPCs when the first synapses are formed in the ventral-lateral marginal zone.

Acetylcholine controls GABA-, glutamate-, and glycine-dependent giant depolarizing potentials that govern spontaneous motoneuron activity at the onset of synaptogenesis in the mouse embryonic spinal cord.

A remarkable feature of early neuronal networks is their endogenous ability to generate spontaneous rhythmic electrical activity independently of any external stimuli. In the mouse embryonic SC, this activity starts at an embryonic age of ∼ 12 d and is characterized by bursts of action potentials recurring every 2-3 min. Although these bursts have been extensively studied using extracellular recordings and are known to play an important role in motoneuron (MN) maturation, the mechanisms driving MN activity at the onset of synaptogenesis are still poorly understood.

Maturation of the GABAergic transmission in normal and pathologic motoneurons.

γ-aminobutyric acid (GABA) acting on Cl(-)-permeable ionotropic type A (GABA(A)) receptors (GABA(A)R) is the major inhibitory neurotransmitter in the adult central nervous system of vertebrates. In immature brain structures, GABA exerts depolarizing effects mostly contributing to the expression of spontaneous activities that are instructive for the construction of neural networks but GABA also acts as a potent trophic factor. In the present paper, we concentrate on brainstem and spinal motoneurons that are largely targeted by GABAergic interneurons, and we bring together data on the switch from excitatory to inhibitory effects of GABA, on the maturation of the GABAergic system and GABA(A)R subunits.

GABA(A) receptor and glycine receptor activation by paracrine/autocrine release of endogenous agonists: more than a simple communication pathway.

It is a common and widely accepted assumption that glycine and GABA are the main inhibitory transmitters in the central nervous system (CNS). But, in the past 20 years, several studies have clearly demonstrated that these amino acids can also be excitatory in the immature central nervous system. In addition, it is now established that both GABA receptors (GABARs) and glycine receptors (GlyRs) can be located extrasynaptically and can be activated by paracrine release of endogenous agonists, such as GABA, glycine, and taurine.

Extrasynaptic and postsynaptic receptors in glycinergic and GABAergic neurotransmission: a division of labor?

Glycine and GABA mediate inhibitory neurotransmission in the spinal cord and central nervous system. The general concept of neurotransmission is now challenged by the contribution of both phasic activation of postsynaptic glycine and GABA(A) receptors (GlyRs and GABA(A)Rs, respectively) and tonic activity of these receptors located at extrasynaptic sites. GlyR and GABA(A)R kinetics depend on several parameters, including subunit composition, subsynaptic localization and activation mode.

Despite GABAergic neurotransmission, GABAergic innervation does not compensate for the defect in glycine receptor postsynaptic aggregation in spastic mice.

In the hypoglossal nucleus of wild-type mice, early mixed glycinergic-GABAergic inhibitory transmission becomes mainly glycinergic during postnatal maturation. In spastic mice (SPA), a model of human hyperekplexic syndrome, an insertion into the gene of the glycine receptor (GlyR) beta subunit results in a decreased accumulation of GlyRs at postsynaptic sites and an impaired glycinergic neurotransmission. In SPA mice displaying a mild phenotype (B6C3Fe strain), a compensatory process involving an increased aggregation of GABA(A) receptors (GABA(A)Rs) at postsynaptic sites was proposed to explain survival of mutant animals until adulthood.

Developmental dissociation of presynaptic inhibitory neurotransmitter and postsynaptic receptor clustering in the hypoglossal nucleus.

At postsynaptic densities of mouse hypoglossal motoneurons, the proportion of glycine receptors co-clustered with GABAA receptors increases from neonatal to adult animals, suggesting that mixed synapses might play a greater role in adult synaptic inhibition. We visualized the presynaptic correlates of these developmental changes using immunocytochemistry. At P5, presynaptic terminals contained glycine and GlyT2 and/or GABA and GAD65, but at P15, the majority of inhibitory terminals contained glycine and GlyT2 only.

Differential sensitivity of two insect GABA-gated chloride channels to dieldrin, fipronil and picrotoxinin.

In the central nervous system of both vertebrates and invertebrates inhibitory neurotransmission is mainly achieved through activation of gamma-aminobutyric acid (GABA) receptors. Extensive studies have established the structural and pharmacological properties of vertebrate GABA receptors. Although the vast majority of insect GABA-sensitive responses share some properties with vertebrate GABAA receptors, peculiar pharmacological properties of these receptors led us to think that several GABA-gated chloride channels are present in insects.