Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

Epilepsy is one of the most common neurological disorders characterized by recurrent seizures. The mechanism of epilepsy remains unclear and previous studies suggest that N-methyl-D-aspartate receptors (NMDARs) play an important role in abnormal discharges, nerve conduction, neuron injury and inflammation, thereby they may participate in epileptogenesis. NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. Despite numerous studies focusing on the role of NMDAR in epilepsy, the relationship appeared to be elusive. In this article, we reviewed the regulation of NMDAR and possible mechanisms of NMDAR in epilepsy and in respect of onset, development, and treatment, trying to provide more evidence for future studies.

Dynamic Mechanism of Epilepsy Generation and Propagation After Ischemic Stroke

Epilepsy is the second largest neurological disease which seriously threatens human life and health. The one important reason of inducing epilepsy is ischemic stroke which causes insufficient oxygen supply from blood vessels to neurons. However, few studies focus on the underlying mechanism of the generation and propagation of epilepsy after ischemic stroke by utilizing modeling methods. To explore the mechanism, this paper establishes a coupled network model consisting of neurons and astrocytes, and introduces a blood vessel to simulate the condition of ischemic stroke. First we study the effect of the degree of vascular blockage on the generation of epilepsy. The results demonstrate that the important reason of epilepsy after ischemic stroke is the disruption of ion concentration gradient. Then we study three factors that influence the epileptic propagation after ischemic stroke: massive glutamate release, excessive receptor activation and high extracellular potassium concentration. The results demonstrate that massive glutamate acting on postsynaptic neurons and the excessive activation of glutamate receptors on postsynaptic neurons promote the epileptic propagation in neuronal population, and massive glutamate acting on astrocytes and excessive activation of metabotropic glutamate receptors on presynaptic neurons inhibit the epileptic propagation, and the potassium uptake by astrocytes suppresses the epileptic propagation. The results are consistent with the experimental phenomena. The simulation results also shed light on the fact that astrocytes have neuroprotective effect. Our results on the generation and propagation of epilepsy after ischemic stroke could offer theoretical guidelines for the treatment of epilepsy after ischemic stroke.

Essential regulatory functions of CaMKII T286 phosphorylation in LTP and two distinct forms of LTD

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates both long-term potentiation and depression (LTP and LTD) of excitatory synapses, two opposing forms of synaptic plasticity induced by strong versus weak stimulation of NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD is prevalent in juvenile hippocampus, but in mature hippocampus, LTD is still readily induced by stimulating metabotropic glutamate receptors (mGluRs). Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation that induces Ca2+-independent autonomous kinase activity. This autophosphorylation (i) accelerated CaMKII movement to excitatory synapses after LTP stimuli and (ii) was required for the movement to inhibitory synapses after NMDAR-LTD stimuli. Similar to NMDAR-LTD, the mGluR-LTD stimuli did not induce any CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Taken together, even though CaMKII T286 autophosphorylation has a longstanding prominent role in LTP, it is also required for both major forms of LTD in hippocampal neurons, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.

The Implication of Glial Metabotropic Glutamate Receptors in Alzheimer’s Disease

: Alzheimer’s disease (AD) was first identified more than 100 years ago and, yet, aspects pertaining its origin as well as the mechanisms underlying disease progression are not well known. To this date, there is no therapeutic approach or disease modifying drug that could halt or at least delay disease progression. Until recently, glial cells were seen as secondary actors in brain homeostasis. Although this view was gradually refuted and the relevance of glial cells for the most diverse brain functions such as synaptic plasticity and neurotransmission was vastly proved, many aspects of its functioning as well as its role in pathological conditions remain poorly understood. Metabotropic glutamate receptors (mGluRs) in glial cells were shown to be involved in neuroinflammation and neurotoxicity. Besides its relevance for glial function, glutamatergic receptors are also central in the pathology of AD and recent studies have shown that glial mGluRs play a role in the establishment and progression of AD. Glial mGluRs influence AD-related alterations in Ca2+ signalling, APP processing and Aβ burden, as well as AD-related neurodegeneration. However, different types of mGluRs play different roles, depending on the cell type and brain region that is being analysed. Therefore, in this review we focus on the current understanding of glial mGluRs and their implication in AD, providing an insight for future therapeutics and identifying existing research gaps worth investigating.

mTORC1 Signaling Pathway Mediates Chronic Stress-Induced Synapse Loss in the Hippocampus

Background: The mechanistic target of rapamycin complex 1 (mTORC1) signaling has served as a promising target for therapeutic intervention of major depressive disorder (MDD), but the mTORC1 signaling underlying MDD has not been well elucidated. In the present study, we investigated whether mTORC1 signaling pathway mediates synapse loss induced by chronic stress in the hippocampus.Methods: Chronic restraint stress-induced depression-like behaviors were tested by behavior tests (sucrose preference test, forced swim test and tail suspension test). Synaptic proteins and alternations of phosphorylation levels of mTORC1 signaling-associated molecules were measured using Western blotting. In addition, mRNA changes of immediate early genes (IEGs) and glutamate receptors were measured by RT-PCR. Rapamycin was used to explore the role of mTORC1 signaling in the antidepressant effects of fluoxetine.Results: After successfully establishing the chronic restraint stress paradigm, we observed that the mRNA levels of some IEGs were significantly changed, indicating the activation of neurons and protein synthesis alterations. Then, there was a significant downregulation of glutamate receptors and postsynaptic density protein 95 at protein and mRNA levels. Additionally, synaptic fractionation assay revealed that chronic stress induced synapse loss in the dorsal and ventral hippocampus. Furthermore, these effects were associated with the mTORC1 signaling pathway-mediated protein synthesis, and subsequently the phosphorylation of associated downstream signaling targets was reduced after chronic stress. Finally, we found that intracerebroventricular infusion of rapamycin simulated depression-like behavior and also blocked the antidepressant effects of fluoxetine.Conclusion: Overall, our study suggests that mTORC1 signaling pathway plays a critical role in mediating synapse loss induced by chronic stress, and has part in the behavioral effects of antidepressant treatment.

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

Focusing on defining metabolite-based inter-tumoral heterogeneity in ovarian cancer, we investigated the metabolic diversity of a panel of high-grade serous ovarian carcinoma (HGSOC) cell-lines using a metabolomics platform that interrogate 731 compounds. Metabolic fingerprinting followed by 2-dimensional and 3-dimensional principal component analysis established the heterogeneity of the HGSOC cells by clustering them into five distinct metabolic groups compared to the fallopian tube epithelial cell line control. An overall increase in the metabolites associated with aerobic glycolysis and phospholipid metabolism were observed in the majority of the cancer cells. A preponderant increase in the levels of metabolites involved in trans-sulphuration and glutathione synthesis was also observed. More significantly, subsets of HGSOC cells showed an increase in the levels of 5-Hydroxytryptamine, γ-aminobutyrate, or glutamate. Additionally, 5-hydroxytryptamin synthesis inhibitor as well as antagonists of γ-aminobutyrate and glutamate receptors prohibited the proliferation of HGSOC cells, pointing to their potential roles as oncometabolites and ligands for receptor-mediated autocrine signaling in cancer cells. Consistent with this role, 5-Hydroxytryptamine synthesis inhibitor as well as receptor antagonists of γ-aminobutyrate and Glutamate-receptors inhibited the proliferation of HGSOC cells. These antagonists also inhibited the three-dimensional spheroid growth of TYKNU cells, a representative HGSOC cell-line. These results identify 5-HT, GABA, and Glutamate as putative oncometabolites in ovarian cancer metabolic sub-type and point to them as therapeutic targets in a metabolomic fingerprinting-based therapeutic strategy.