Not GABA But Glycine Mediates Segmental, Propriospinal, and Bulbospinal Postsynaptic Inhibition in Adult Mouse Spinal Forelimb Motor Neurons

Jiang, Juan; Alstermark, B.

doi:10.1523/jneurosci.1627-14.2015

Cited by 7 publications

(4 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Proposed Mechanism of Hyperekplexia by Gain-of-function GLRA1 Mutants-Synaptic inhibition in adult spinal motor neurons is mediated exclusively by glycine (40,41) or by a combination of glycine and GABA (42,43). The chloride concentration in adult neurons is normally very low, and as a result small increases in the chloride influx rate can have a significant effect on the strength, or even polarity, of glycinergic signaling (44).…”

Section: Discussionmentioning

confidence: 99%

Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia

Zhang

Bode

Nguyen

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hyperekplexia is a rare human neuromotor disorder caused by mutations that impair the efficacy of glycinergic inhibitory neurotransmission. Loss-of-function mutations in the GLRA1 or GLRB genes, which encode the α1 and β glycine receptor (GlyR) subunits, are the major cause. Paradoxically, gain-of-function GLRA1 mutations also cause hyperekplexia, although the mechanism is unknown. Here we identify two new gain-of-function mutations (I43F and W170S) and characterize these along with known gain-of-function mutations (Q226E, V280M, and R414H) to identify how they cause hyperekplexia. Using artificial synapses, we show that all mutations prolong the decay of inhibitory postsynaptic currents (IPSCs) and induce spontaneous GlyR activation. As these effects may deplete the chloride electrochemical gradient, hyperekplexia could potentially result from reduced glycinergic inhibitory efficacy. However, we consider this unlikely as the depleted chloride gradient should also lead to pain sensitization and to a hyperekplexia phenotype that correlates with mutation severity, neither of which is observed in patients with GLRA1 hyperekplexia mutations. We also rule out small increases in IPSC decay times (as caused by W170S and R414H) as a possible mechanism given that the clinically important drug, tropisetron, significantly increases glycinergic IPSC decay times without causing motor side effects. A recent study on cultured spinal neurons concluded that an elevated intracellular chloride concentration late during development ablates α1β glycinergic synapses but spares GABAergic synapses. As this mechanism satisfies all our considerations, we propose it is primarily responsible for the hyperekplexia phenotype.

show abstract

Section: Discussionmentioning

confidence: 99%

Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia

Zhang

Bode

Nguyen

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Despite its established importance, only few studies have addressed the diversity and role of inhibition within brainstem circuits. As opposed to rostral brain areas, many glycinergic neurons exist in the brainstem, which can mediate long range communication to spinal motor neurons 28 . There is also evidence for important roles of intra-brainstem excitation-inhibition balance for orofacial behaviors 29 .…”

Section: Circuit Principles For Body Movementsmentioning

confidence: 99%

Networking brainstem and basal ganglia circuits for movement

2022

View full text Add to dashboard Cite

Execution and learning of diverse movements involve neuronal networks distributed throughout the nervous system. Brainstem and basal ganglia are key for processing motor information. Both harbor functionally-specialized populations stratified based on axonal projections, synaptic inputs and gene expression, revealing a correspondence between circuit anatomy and function at a high level of granularity. Neuronal populations within both structures form multi-step processing chains dedicated to the execution of specific movements. However, the connectivity and communication between these two structures is only just beginning to be revealed. Brainstem and basal ganglia are also embedded into wider networks, and systems-level loops. Important networking components include broadcasting neurons in cortex, cerebellar output neurons, and midbrain dopaminergic neurons. Action-specific circuits can be enhanced, vetoed, work in synergy or competition with others or undergo plasticity to allow for adaptive behavior. We propose that this highly specific organization of circuits in the motor system is a core ingredient for supporting behavioral specificity, and at the same time providing an adequate substrate for behavioral flexibility.

show abstract

“…1,2 As an inhibitory neurotransmitter, it activates ionotropic glycine receptors (GlyRs), leading to post-synaptic hyperpolarization and inhibition of neuronal activity, predominantly in caudal regions of the CNS. 3,4 In addition, glycine acts as an obligatory co-agonist at excitatory glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype, which are prevalent throughout the CNS. 1,2 Extracellular glycine concentrations are regulated by two glycine transporters, GLYT1 (encoded by SLC6A9 [MIM: 601019]) and GLYT2 (encoded by SLC6A5 [MIM: 604159]).…”

mentioning

confidence: 99%

Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine

Kurolap

Armbruster

Hershkovitz

et al. 2016

The American Journal of Human Genetics

View full text Add to dashboard Cite

Glycine is a major neurotransmitter that activates inhibitory glycine receptors and is a co-agonist for excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors. Two transporters, GLYT1 and GLYT2, regulate extracellular glycine concentrations within the CNS. Dysregulation of the extracellular glycine has been associated with hyperekplexia and nonketotic hyperglycinemia. Here, we report four individuals from two families who presented at birth with facial dysmorphism, encephalopathy, arthrogryposis, hypotonia progressing to hypertonicity with startle-like clonus, and respiratory failure. Only one individual survived the respiratory failure and was weaned off ventilation but has significant global developmental delay. Mildly elevated cerebrospinal fluid (CSF) glycine and normal serum glycine were observed in two individuals. In both families, we identified truncating mutations in SLC6A9, encoding GLYT1. We demonstrate that pharmacologic or genetic abolishment of GlyT1 activity in mice leads to mildly elevated glycine in the CSF but not in blood. Additionally, previously reported slc6a9-null mice and zebrafish mutants also display phenotypes consistent with the affected individuals we examined. Our data suggest that truncating SLC6A9 mutations lead to a distinct human neurological syndrome hallmarked by mildly elevated CSF glycine and normal serum glycine.

show abstract

Not GABA But Glycine Mediates Segmental, Propriospinal, and Bulbospinal Postsynaptic Inhibition in Adult Mouse Spinal Forelimb Motor Neurons

Cited by 7 publications

References 34 publications

Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia

Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia

Networking brainstem and basal ganglia circuits for movement

Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine

Contact Info

Product

Resources

About