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1.
Front Mol Neurosci ; 16: 1018530, 2023.
Article in English | MEDLINE | ID: mdl-37284465

ABSTRACT

The monovalent cations sodium and potassium are crucial for the proper functioning of excitable cells, but, in addition, other monovalent alkali metal ions such as cesium and lithium can also affect neuronal physiology. For instance, there have been recent reports of adverse effects resulting from self-administered high concentrations of cesium in disease conditions, prompting the Food and Drug Administration (FDA) to issue an alert concerning cesium chloride. As we recently found that the monovalent cation NH4+ activates glycine receptors (GlyRs), we investigated the effects of alkali metal ions on the function of the GlyR, which belongs to one of the most widely distributed neurotransmitter receptors in the peripheral and central nervous systems. Whole-cell voltage clamp electrophysiology was performed with HEK293T cells transiently expressing different splice and RNA-edited variants of GlyR α2 and α3 homopentameric channels. By examining the influence of various milli- and sub-millimolar concentrations of lithium, sodium, potassium, and cesium on these GlyRs in comparison to its natural ligand glycine (0.1 mM), we could show that cesium activates GlyRs in a concentration- and post-transcriptional-dependent way. Additionally, we conducted atomistic molecular dynamic simulations on GlyR α3 embedded in a membrane bilayer with potassium and cesium, respectively. The simulations revealed slightly different GlyR-ion binding profiles for potassium and cesium, identifying interactions near the glycine binding pocket (potassium and cesium) and close to the RNA-edited site (cesium) in the extracellular GlyR domain. Together, these findings show that cesium acts as an agonist of GlyRs.

2.
Hum Mol Genet ; 31(6): 901-913, 2022 03 21.
Article in English | MEDLINE | ID: mdl-34617111

ABSTRACT

Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition is linked to epilepsy. Gephyrin (Geph) is the principal scaffolding protein at inhibitory synapses and is essential for postsynaptic clustering of glycine (GlyRs) and GABA type A receptors. Consequently, gephyrin is crucial for maintaining the relationship between excitation and inhibition in normal brain function and mutations in the gephyrin gene (GPHN) are associated with neurodevelopmental disorders and epilepsy. We identified bi-allelic variants in the GPHN gene, namely the missense mutation c.1264G > A and splice acceptor variant c.1315-2A > G, in a patient with developmental and epileptic encephalopathy. We demonstrate that the splice acceptor variant leads to nonsense-mediated mRNA decay. Furthermore, the missense variant (D422N) alters gephyrin structure, as examined by analytical size exclusion chromatography and circular dichroism-spectroscopy, thus leading to reduced receptor clustering and sensitivity towards calpain-mediated cleavage. In addition, both alterations contribute to an observed reduction of inhibitory signal transmission in neurons, which likely contributes to the pathological encephalopathy.


Subject(s)
Brain Diseases , Epilepsy , Brain Diseases/metabolism , Carrier Proteins/metabolism , Epilepsy/metabolism , Humans , Membrane Proteins/metabolism , Receptors, GABA-A/metabolism , Synapses/metabolism
3.
Cells ; 10(9)2021 09 03.
Article in English | MEDLINE | ID: mdl-34571950

ABSTRACT

A tight regulation of the balance between inhibitory and excitatory synaptic transmission is a prerequisite for synaptic plasticity in neuronal networks. In this context, the neurite growth inhibitor membrane protein Nogo-A modulates synaptic plasticity, strength, and neurotransmitter receptor dynamics. However, the molecular mechanisms underlying these actions are unknown. We show that Nogo-A loss-of-function in primary mouse hippocampal cultures by application of a function-blocking antibody leads to higher excitation following a decrease in GABAARs at inhibitory and an increase in the GluA1, but not GluA2 AMPAR subunit at excitatory synapses. This unbalanced regulation of AMPAR subunits results in the incorporation of Ca2+-permeable GluA2-lacking AMPARs and increased intracellular Ca2+ levels due to a higher Ca2+ influx without affecting its release from the internal stores. Increased neuronal activation upon Nogo-A loss-of-function prompts the phosphorylation of the transcription factor CREB and the expression of c-Fos. These results contribute to the understanding of the molecular mechanisms underlying the regulation of the excitation/inhibition balance and thereby of plasticity in the brain.


Subject(s)
Calcium/metabolism , Hippocampus/metabolism , Neurons/metabolism , Nogo Proteins/metabolism , Animals , Excitatory Postsynaptic Potentials/physiology , Female , Male , Mice , Mice, Inbred C57BL , Neuronal Plasticity/physiology , Receptors, AMPA/metabolism , Synapses/metabolism , Synaptic Transmission/physiology
4.
Cell Rep ; 29(3): 671-684.e6, 2019 10 15.
Article in English | MEDLINE | ID: mdl-31618635

ABSTRACT

Precisely controlling the excitatory and inhibitory balance is crucial for the stability and information-processing ability of neuronal networks. However, the molecular mechanisms maintaining this balance during ongoing sensory experiences are largely unclear. We show that Nogo-A signaling reciprocally regulates excitatory and inhibitory transmission. Loss of function for Nogo-A signaling through S1PR2 rapidly increases GABAAR diffusion, thereby decreasing their number at synaptic sites and the amplitude of GABAergic mIPSCs at CA3 hippocampal neurons. This increase in GABAAR diffusion rate is correlated with an increase in Ca2+ influx and requires the calcineurin-mediated dephosphorylation of the γ2 subunit at serine 327. These results suggest that Nogo-A signaling rapidly strengthens inhibitory GABAergic transmission by restricting the diffusion dynamics of GABAARs. Together with the observation that Nogo-A signaling regulates excitatory transmission in an opposite manner, these results suggest a crucial role for Nogo-A signaling in modulating the excitation and inhibition balance to restrict synaptic plasticity.


Subject(s)
Nogo Proteins/metabolism , Receptors, GABA-A/metabolism , Animals , Antibodies, Blocking/immunology , Calcineurin/metabolism , Calcium/metabolism , Cells, Cultured , Female , Hippocampus/cytology , Hippocampus/metabolism , Male , Mice , Mice, Inbred C57BL , Nogo Proteins/immunology , Patch-Clamp Techniques , Protein Subunits/genetics , Protein Subunits/metabolism , Rats , Rats, Wistar , Receptors, GABA-A/genetics , Signal Transduction , Sphingosine-1-Phosphate Receptors/antagonists & inhibitors , Sphingosine-1-Phosphate Receptors/metabolism , Synapses/metabolism , Synaptic Transmission
5.
Neurobiol Learn Mem ; 138: 154-163, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27349794

ABSTRACT

Behavioral learning has been shown to involve changes in the function and structure of synaptic connections of the central nervous system (CNS). On the other hand, the neuronal circuitry in the mature brain is characterized by a high degree of stability possibly providing a correlate for long-term storage of information. This observation indicates the requirement for a set of molecules inhibiting plasticity and promoting stability thereby providing temporal and spatial specificity to plastic processes. Indeed, signaling of Nogo-A via its receptors has been shown to play a crucial role in restricting activity-dependent functional and structural plasticity in the adult CNS. However, whether Nogo-A controls learning and memory formation and what are the cellular and molecular mechanisms underlying this function is still unclear. Here we show that Nogo-A signaling controls spatial learning and reference memory formation upon training in the Morris water maze and negatively modulates structural changes at spines in the mouse hippocampus. Learning processes and the correlated structural plasticity have been shown to involve changes in excitatory as well as in inhibitory neuronal connections. We show here that Nogo-A is highly expressed not only in excitatory, but also in inhibitory, Parvalbumin positive neurons in the adult hippocampus. By this means our current and previous data indicate that Nogo-A loss-of-function positively influences spatial learning by priming the neuronal structure to a higher plasticity level. Taken together our results link the role of Nogo-A in negatively regulating plastic processes to a physiological function in controlling learning and memory processes in the mature hippocampus and open the interesting possibility that it might mainly act by controlling the function of the hippocampal inhibitory circuitry.


Subject(s)
Hippocampus/metabolism , Memory/physiology , Neuronal Plasticity/physiology , Nogo Proteins/metabolism , Spatial Learning/physiology , Animals , Cognition/physiology , Dendritic Spines/metabolism , Male , Mice , Mice, Knockout , Neural Inhibition/physiology , Nogo Proteins/genetics , Parvalbumins/metabolism
6.
Hippocampus ; 26(6): 816-31, 2016 06.
Article in English | MEDLINE | ID: mdl-26748478

ABSTRACT

Nogo-A and its receptors have been shown to control synaptic plasticity, including negatively regulating long-term potentiation (LTP) in the cortex and hippocampus at a fast time scale and restraining experience-dependent turnover of dendritic spines over days. However, the molecular mechanisms and the precise time course mediating these actions of Nogo-A are largely unexplored. Here we show that Nogo-A signaling in the adult nervous system rapidly modulates the spine actin cytoskeleton within minutes to control structural plasticity at dendritic spines of CA3 pyramidal neurons. Indeed, acute Nogo-A loss-of-function transiently increases F-actin stability and results in an increase in dendritic spine density and length. In addition, Nogo-A acutely restricts AMPAR insertion and mEPSC amplitude at hippocampal synaptic sites. These data indicate a crucial function of Nogo-A in modulating the very tight balance between plasticity and stability of the neuronal circuitry underlying learning processes and the ability to store long-term information in the mature CNS. © 2016 Wiley Periodicals, Inc.


Subject(s)
Actins/metabolism , Dendritic Spines/metabolism , Nogo Proteins/metabolism , Animals , CA3 Region, Hippocampal/metabolism , Cells, Cultured , Excitatory Postsynaptic Potentials/physiology , Mice, Inbred C57BL , Miniature Postsynaptic Potentials/physiology , Neuronal Plasticity/physiology , Pyramidal Cells/physiology , Rats, Wistar , Receptors, AMPA/metabolism , Tissue Culture Techniques
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