Impaired D-Serine-Mediated Cotransmission Mediates Cognitive Dysfunction in Epilepsy

K, Klatte; Kirschstein, Timo; Otte, David M.; Pothmann, Leonie; Müller, Luisa; Tokay, Tursonjan; Kober, Maria; Uebachs, Mischa; Zimmer, Andreas; Beck, Hanno

doi:10.1523/jneurosci.5423-12.2013

Cited by 43 publications

(41 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, disruption of adenosine and D‐serine signaling mechanisms associates with post‐synaptic molecular changes and lower seizure threshold (Klatte et al . ; Boison ). Finally, very recent evidence has shown a role for the endocannabinoid system in regulating susceptibility to epilepsy (reviewed in Soltesz et al .…”

Section: Synapse Dysfunction In Neurodevelopmental Disordersmentioning

confidence: 99%

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Lepeta

Lourenco

Schweitzer

et al. 2016

Journal of Neurochemistry

296

220

View full text Add to dashboard Cite

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in diseaseassociated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders.

show abstract

Section: Synapse Dysfunction In Neurodevelopmental Disordersmentioning

confidence: 99%

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Lepeta

Lourenco

Schweitzer

et al. 2016

Journal of Neurochemistry

296

220

View full text Add to dashboard Cite

show abstract

“…Recently, Klatte and colleagues (Klatte et al . ) found in an experimental model of TLE that memory defects are associated with a reduction in the CNS levels of d ‐serine because of decreased synthesis by SR and increased degradation by DAAO (Klatte et al . ).…”

Section: Structure and Subunit Diversity Of Nmdars In The Cnsmentioning

confidence: 99%

“…) found in an experimental model of TLE that memory defects are associated with a reduction in the CNS levels of d ‐serine because of decreased synthesis by SR and increased degradation by DAAO (Klatte et al . ). This weaker d ‐serine content leads to a desaturation of the co‐agonist binding site of synaptic and extrasynaptic NMDARs which in turn results in severe LTP impairment and spatial learning deficits in epileptic animals (Klatte et al .…”

Section: Structure and Subunit Diversity Of Nmdars In The Cnsmentioning

confidence: 99%

Time and space profiling of NMDA receptor co‐agonist functions

Mothet

Bail

Billard

2015

Journal of Neurochemistry

View full text Add to dashboard Cite

The N-Methyl D-Aspartic acid (NMDA) receptors (NMDAR) are key tetrameric ionotropic glutamate receptors that transduce glutamatergic signals throughout the central nervous system (CNS) and spinal cord. Although NMDARs are diverse in their subunit composition, subcellular localization, and biophysical and pharmacological properties, their activation always requires the binding of a co-agonist that has long been thought to be glycine. However, intense research over the last decade has challenged this classical model by showing that another amino acid, D-serine, is the preferential co-agonist for a subset of synaptic NMDARs in many areas of the adult brain. Nowadays, a totally new picture of glutamatergic synapses at work is emerging where both glycine and D-serine are involved in a complex interplay to regulate NMDAR functions in the CNS following time and space constraints. The purpose of this review was to highlight the particular role of each co-agonist in modulating NMDAR-dependent activities in healthy and diseased brains. We have herein integrated our most advanced knowledge of how glycine and D-serine may orchestrate synapse dynamics and drive neuronal network activity in a time-and synapse-specific manner and how changes in synaptic availability of these amino acids may contribute to cognitive impairments such as those associated with healthy aging, epilepsy, and schizophrenia.

show abstract

“…For example, D-serine potentiates NMDA-induced convulsions but antagonizes electroshock-induced tonic-clinic seizures in mice. 40) Regardless of whether M22 affects NMDA receptors, however, our results showed that M22 ultimately elevated the seizure threshold in the mouse maximal electroshock model. Additional evidence is required to establish the role of the strychnine-insensitive binding site in the pathogenesis of seizures.…”

Section: Discussionmentioning

confidence: 65%

A Highly Selective Inhibitor of Glycine Transporter-1 Elevates the Threshold for Maximal Electroshock-Induced Tonic Seizure in Mice

Zhao

Tao

Xian

et al. 2016

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Many anti-epileptic drugs (AEDs) that mainly target ion channels or post-synaptic receptors are in clinical use, but a proportion of patients are resistant to these traditional AEDs and experience repeated severe break-out seizures. Given its involvement in the etiology of epilepsy, the neurotransmitter glycine may serve as a novel target for epilepsy treatment. Increasing evidence suggests that inhibitors of glycine transporter 1 (GlyT1) exhibit anti-seizure properties in mouse models and show potential as anti-convulsions drugs. In the present study, we investigated the effect of a highly selective GlyT1 inhibitor (named M22) on glycine transport kinetics using a radioactive substrate uptake assay and investigated the anti-seizure effects of M22 on the maximal electroshock seizure threshold (MEST) test and the timed intravenous (i.v.) pentylenetetrazole (PTZ) intravenous test. Our results demonstrate that M22 was capable of elevating the seizure threshold in the MEST test but did not alter the seizure threshold in the PTZ i.v. test. Strychnine, an inhibitor of glycine receptor activity, reversed the threshold elevation at a subconvulsive dosage (0.1 mg/kg subcutaneously) in the MEST test and did not affect M22 plasma levels in mice, suggesting that the anti-seizure effect in this model may be mediated by increased glycine receptor activity. Moreover, M22 administration did not influence motor function and coordination in mice. In combination with the previously reported excellent pharmacokinetic features of M22, our present results suggested that M22 has the potential to serve as a new anticonvulsive drug or as a lead compound for the development of AEDs.

show abstract

Impaired D-Serine-Mediated Cotransmission Mediates Cognitive Dysfunction in Epilepsy

Cited by 43 publications

References 61 publications

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Time and space profiling of NMDA receptor co‐agonist functions

A Highly Selective Inhibitor of Glycine Transporter-1 Elevates the Threshold for Maximal Electroshock-Induced Tonic Seizure in Mice

Contact Info

Product

Resources

About