Vitamin D in Central Nervous System: Implications for Neurological Disorders.

Vitamin D, obtained from diet or synthesized internally as cholecalciferol and ergocalciferol, influences bodily functions through its most active metabolite and the vitamin D receptor. Recent research has uncovered multiple roles for vitamin D in the central nervous system, impacting neural development and maturation, regulating the dopaminergic system, and controlling the synthesis of neural growth factors. This review thoroughly examines these connections and investigates the consequences of vitamin D deficiency in neurological disorders, particularly neurodegenerative diseases. The potential benefits of vitamin D supplementation in alleviating symptoms of these diseases are evaluated alongside a discussion of the controversial findings from previous intervention studies. The importance of interpreting these results cautiously is emphasised. Furthermore, the article proposes that additional randomised and well-designed trials are essential for gaining a deeper understanding of the potential therapeutic advantages of vitamin D supplementation for neurological disorders. Ultimately, this review highlights the critical role of vitamin D in neurological well-being and highlights the need for further research to enhance our understanding of its function in the brain.

Functional Metaplasticity of Hippocampal Schaffer Collateral-CA1 Synapses Is Reversed in Chronically Epileptic Rats.

Spatial learning and associating spatial information with individual experience are crucial for rodents and higher mammals. Hence, studying the cellular and molecular cascades involved in the key mechanism of information storage in the brain, synaptic plasticity, has led to enormous knowledge in this field. A major open question applies to the interdependence between synaptic plasticity and its behavioral correlates. In this context, it has become clear that behavioral aspects may impact subsequent synaptic plasticity, a phenomenon termed behavioral metaplasticity. Here, we trained control and pilocarpine-treated chronically epileptic rats of two different age groups (adolescent and adult) in a spatial memory task and subsequently tested long-term potentiation (LTP) in vitro at Schaffer collateral-CA1 synapses. As expected, memory acquisition in the behavioral task was significantly impaired both in pilocarpine-treated animals and in adult controls. Accordingly, these groups, without being tested in the behavioral training task, showed reduced CA1-LTP levels compared to untrained young controls. Spatial memory training significantly reduced subsequent CA1-LTP in vitro in the adolescent control group yet enhanced CA1-LTP in the adult pilocarpine-treated group. Such training in the adolescent pilocarpine-treated and adult control groups resulted in intermediate changes. Our study demonstrates age-dependent functional metaplasticity following a spatial memory training task and its reversal under pathological conditions.

P2Y receptor-mediated transient relaxation of rat longitudinal ileum preparations involves phospholipase C activation, intracellular Ca(2+) release and SK channel activation.

AIM: Purinergic signaling plays a major role in the enteric nervous system, where it governs gut motility through a number of P2X and P2Y receptors. The aim of this study was to investigate the P2Y receptor-mediated motility in rat longitudinal ileum preparations. METHODS: Ileum smooth muscle strips were prepared from rats, and fixed in an organ bath. Isometric contraction and relaxation responses of the muscle strips were measured with force transducers. Drugs were applied by adding of stock solutions to the organ bath to yield the individual final concentrations. RESULTS: Application of the non-hydrolyzable P2 receptor agonists α,ß-Me-ATP or 2-Me-S-ADP (10, 100 µmol/L) dose-dependently elicited a transient relaxation response followed by a sustained contraction. The relaxation response was largely blocked by SK channel blockers apamin (500 nmol/L) and UCL1684 (10 µmol/L), PLC inhibitor U73122 (100 µmol/L), IP3 receptor blocker 2-APB (100 µmol/L) or sarcoendoplasmic Ca(2+) ATPase inhibitor thapsigargin (1 µmol/L), but not affected by atropine, NO synthase blocker L-NAME or tetrodotoxin. Furthermore, α,ß-Me-ATP-induced relaxation was suppressed by P2Y1 receptor antagonist MRS2179 (50 µmol/L) or P2Y13 receptor antagonist MRS2211 (100 µmol/L), and was abolished by co-application of the two antagonists, whereas 2-Me-S-ADP-induced relaxation was abolished by P2Y6 receptor antagonist MRS2578 (50 µmol/L). In addition, P2Y1 receptor antagonist MRS2500 (1 µmol/L) not only abolished α,ß-Me-ATP-induced relaxation, but also suppressed 2-Me-S-ADP-induced relaxation. CONCLUSION: P2Y receptor agonist-induced transient relaxation of rat ileum smooth muscle strips is mediated predominantly by P2Y1 receptor, but also by P2Y6 and P2Y13 receptors, and involves PLC, IP3, Ca(2+) release and SK channel activation, but is independent of acetylcholine and NO release.

Status Epilepticus Enhances Depotentiation after Fully Established LTP in an NMDAR-Dependent but GluN2B-Independent Manner.

N-Methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) can be reversed by low-frequency stimulation (LFS) referred to as depotentiation (DP). We previously found GluN2B upregulated in CA1 neurons from post-status epilepticus (post-SE) tissue associated with an enhanced LTP. Here, we tested whether LFS-induced DP is also altered in pathological GluN2B upregulation. Although LTP was enhanced in post-SE tissue, LTP was significantly reversed in this tissue, but not in controls. We next tested the effect of the GluN2B subunit-specific blocker Ro 25-6981 (1 µM) on LFS-DP. As expected, LFS had no effect on synaptic strength in the presence of the GluN2B blocker in control tissue. In marked contrast, LFS-DP was also attained in post-SE tissue indicating that GluN2B was obviously not involved in depotentiation. To test for NMDA receptor-dependence, we applied the NMDA receptor antagonist D-AP5 (50 µM) prior to LFS and observed that DP was abolished in both control and post-SE tissue confirming NMDA receptor involvement. These results indicate that control Schaffer collateral-CA1 synapses cannot be depotentiated after fully established LTP, but LFS was able to reverse LTP significantly in post-SE tissue. However, while LFS-DP clearly required NMDA receptor activation, GluN2B-containing NMDA receptors were not involved in this form of depotentiation.

Impaired D-serine-mediated cotransmission mediates cognitive dysfunction in epilepsy.

The modulation of synaptic plasticity by NMDA receptor (NMDAR)-mediated processes is essential for many forms of learning and memory. Activation of NMDARs by glutamate requires the binding of a coagonist to a regulatory site of the receptor. In many forebrain regions, this coagonist is d-serine. Here, we show that experimental epilepsy in rats is associated with a reduction in the CNS levels of d-serine, which leads to a desaturation of the coagonist binding site of synaptic and extrasynaptic NMDARs. In addition, the subunit composition of synaptic NMDARs changes in chronic epilepsy. The desaturation of NMDARs causes a deficit in hippocampal long-term potentiation, which can be rescued with exogenously supplied d-serine. Importantly, exogenous d-serine improves spatial learning in epileptic animals. These results strongly suggest that d-serine deficiency is important in the amnestic symptoms of temporal lobe epilepsy. Our results point to a possible clinical utility of d-serine to alleviate these disease manifestations.

NMDA receptor-dependent metaplasticity by high-frequency magnetic stimulation.

High-frequency magnetic stimulation (HFMS) can elicit N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) at Schaffer collateral-CA1 pyramidal cell synapses. Here, we investigated the priming effect of HFMS on the subsequent magnitude of electrically induced LTP in the CA1 region of rat hippocampal slices using field excitatory postsynaptic potential (fEPSP) recordings. In control slices, electrical high-frequency conditioning stimulation (CS) could reliably induce LTP. In contrast, the same CS protocol resulted in long-term depression when HFMS was delivered to the slice 30 min prior to the electrical stimulation. HFMS-priming was diminished when applied in the presence of the metabotropic glutamate receptor antagonists (RS)-α-methylserine-O-phosphate (MSOP) and (RS)-α-methyl-4-carboxyphenylglycine (MCPG). Moreover, when HFMS was delivered in the presence of the NMDA receptor-antagonist D-2-amino-5-phosphonovalerate (50 µM), CS-induced electrical LTP was again as high as under control conditions in slices without priming. These results demonstrate that HFMS significantly reduced the propensity of subsequent electrical LTP and show that both metabotropic glutamate and NMDA receptor activation were involved in this form of HFMS-induced metaplasticity.

Enhanced NMDA receptor-dependent LTP in the epileptic CA1 area via upregulation of NR2B.

Impairment of synaptic plasticity such as long-term potentiation (LTP) is a common finding in various animal models of a number of neurodegenerative disorders. While cognitive deficits associated with these models are plausibly attributed to impaired plasticity, it is an intriguing question whether learning impairment correlates in general with compromised synaptic plasticity. In the present study, we have addressed this issue and discovered an enhancement of theta-burst stimulation-induced LTP at Schaffer collateral-CA1 synapses from chronically epileptic animals. The LTP enhancement was abolished by the NMDA receptor 2B (NR2B) blocker Ro 25-6981 (1µM) while it was preserved following application of the NR2A blocker NVP-AAM077 (50nM). Moreover, pharmacological characterization of intracellularly recorded excitatory postsynaptic potentials (EPSP) from CA1 pyramidal neurons indicated an increased NR2B/NR2A ratio in epileptic tissue, and NMDA receptor mediated excitatory postsynaptic currents showed significantly longer decay times. Quantitative reverse-transcriptase PCR confirmed the transcriptional up-regulation of NR2B-mRNA in chronically epileptic animals. To test the significance for epileptiform activity, recurrent epileptiform discharges (REDs) in the CA1 area induced by bath application of either high K(+) (8mM) plus gabazine (5µM) or 4-aminopyridine (50µM), were also characterized pharmacologically. While in control slices the presence of Ro 25-6981 had no effect on the RED frequency, NR2B inhibition significantly increased epileptic activity in tissue from epileptic animals. Our results demonstrate that CA1 synapses in chronically epileptic tissue can undergo an LTP enhancement due to an NR2B up-regulation in CA1 pyramidal neurons. On the network level, this up-regulation appears to be a compensatory process, since blockade of these receptors leaves the tissue more susceptible to hyperexcitability.

ZD7288 enhances long-term depression at early postnatal medial perforant path-granule cell synapses.

Hyperpolarization-activated, cyclic nucleotide-gated nonselective (HCN) channels modulate both membrane potential and resistance and play a significant role in synaptic plasticity. We compared the influence of HCN channels on long-term depression (LTD) at the medial perforant path-granule cell synapse in early postnatal (P9-15) and adult (P30-60) rats. LTD was elicited in P9-15 slices using low-frequency stimulation (LFS, 900 pulses, 1 Hz; 80 ± 4% of baseline). Application of the specific HCN channel blocker ZD7288 (10 µM) before LFS significantly enhanced LTD (62 ± 4%; P < 0.01), showing HCN channels restrain LTD induction. However, when ZD7288 was applied after LFS, LTD was similar to control values and significantly different from the values obtained with ZD7288 application before LFS (81 ± 5%; P < 0.01), indicating that HCN channels do not modulate LTD expression. LTD in slices from adult rats were only marginally lower compared to those in P9-15 slices (85 ± 6%), but bath application of ZD7288 prior to LFS resulted in the same amount of LTD (85 ± 5%). HCN channels in adult tissue hence lose their modulatory effect. In conclusion, we found that HCN channels at the medial perforant path-granule cell synapse compromise LFS-associated induction, but not expression of LTD in early postnatal, but not in adult, rats.

Neuroprotective and anti-epileptic potentials of genus Artemisia L.

The Genus Artemisia L. is one of the largest genera in the Asteraceae family growing wild over in Europe, North America, and Central Asia and has been widely used in folk medicine for the treatment of various ailments. Phytochemical and psychopharmacological studies indicated that the genus Artemisia extracts contain various antioxidant and anti-inflammatory compounds and possess antioxidant, anti-inflammatory, antimicrobial, antimalarial, and antitumor activity. Recently, increasing experimental studies demonstrated that many Artemisia extracts offer a great antiepileptic potential, which was attributed to their bioactive components via various mechanisms of action. However, detailed literature on the antiepileptic properties of the genus Artemisia and its mechanism of action is segregated. In this review, we tried to gather the detailed neuroprotective and antiepileptic properties of the genus Artemisia and its possible underlying mechanisms. In this respect, 63 articles were identified in the PubMed and Google scholars databases, from which 18 studies were examined based on the pharmacological use of the genus Artemisia species in epilepsy. The genus Artemisia extracts have been reported to possess antioxidant, anti-inflammatory, neurotransmitter-modulating, anti-apoptotic, anticonvulsant, and pro-cognitive properties by modulating oxidative stress caused by mitochondrial ROS production and an imbalance of antioxidant enzymes, by protecting mitochondrial membrane potential required for ATP production, by upregulating GABA-A receptor and nACh receptor activities, and by interfering with various anti-inflammatory and anti-apoptotic signaling pathways, such as mitochondrial apoptosis pathway, ERK/CREB/Bcl-2 pathway and Nrf2 pathway. This review provides detailed information about some species of the genus Artemisia as potential antiepileptic agents. Hence, we recommend further investigations on the purification and identification of the most biological effective compounds of Artemisia and the mechanisms of their action to cure epilepsy and other neurological diseases.

The vasoactive peptides urotensin II and urotensin II-related peptide regulate astrocyte activity through common and distinct mechanisms: involvement in cell proliferation.

UII (urotensin II) and its paralogue URP (UII-related peptide) are two vasoactive neuropeptides whose respective central actions are currently unknown. In the present study, we have compared the mechanism of action of URP and UII on cultured astrocytes. Competition experiments performed with [125I]UII showed the presence of very-high- and high-affinity binding sites for UII, and a single high-affinity site for URP. Both UII and URP provoked a membrane depolarization accompanied by a decrease in input resistance, stimulated the release of endozepines, neuropeptides specifically produced by astroglial cells, and generated an increase in [Ca2+]c (cytosolic Ca2+ concentration). The UII/URP-induced [Ca2+]c elevation was PTX (pertussis toxin)-insensitive, and was blocked by the PLC (phospholipase C) inhibitor U73122 or the InsP3 channel blocker 2-APB (2-aminoethoxydiphenylborane). The addition of the Ca2+ chelator EGTA reduced the peak and abolished the plateau phase, whereas the T-type Ca2+ channel blocker mibefradil totally inhibited the Ca2+ response evoked by both peptides. However, URP and UII induced a mono- and bi-phasic dose-dependent increase in [Ca2+]c and provoked short- and long-lasting Ca2+ mobilization respectively. Similar mono- and bi-phasic dose-dependent increases in [3H]inositol incorporation into polyphosphoinositides in astrocytes was obtained, but the effect of UII was significantly reduced by PTX, although BRET (bioluminescence resonance energy transfer) experiments revealed that both UII and URP recruited Galphao-protein. Finally, UII, but not URP, exerted a dose-dependent mitogenic activity on astrocytes. Therefore we described that URP and UII exert not only similar, but also divergent actions on astrocyte activity, with UII exhibiting a broader range of activities at physiological peptide concentrations.

Plant Extract of Limonium gmelinii Attenuates Oxidative Responses in Neurons, Astrocytes, and Cerebral Endothelial Cells In Vitro and Improves Motor Functions of Rats after Middle Cerebral Artery Occlusion.

There are numerous publications demonstrating that plant polyphenols can reduce oxidative stress and inflammatory processes in the brain. In the present study we have investigated the neuroprotective effect of plant extract isolated from the roots of L. gmelinii since it contains a rich source of polyphenols and other biologically active compounds. We have applied an oxidative and inflammatory model induced by NMDA, H2O2, and TNF-α in human primary neurons and astrocytes, and mouse cerebral endothelial cell (CECs) line in vitro. The levels of ROS generation, NADPH oxidase activation, P-selectin expression, and activity of ERK1/2 were evaluated by quantitative immunofluorescence analysis, confocal microscopy, and MAPK assay. In vivo, sensorimotor functions in rats with middle cerebral artery occlusion (MCAO) were assessed. In neurons NMDA induced overproduction of ROS, in astrocytes TNF-α initiated ROS generation, NADPH oxidase activation, and phosphorylation of ERK1/2. In CECs, the exposure by TNF-α induced oxidative stress and triggered the accumulation of P-selectin on the surface of the cells. In turn, pre-treatment of the cells with the extract of L. gmelinii suppressed oxidative stress in all cell types and pro-inflammatory responses in astrocytes and CECs. In vivo, the treatment with L. gmelinii extract improved motor activity in rats with MCAO.

HCN1 channels constrain DHPG-induced LTD at hippocampal Schaffer collateral-CA1 synapses.

HCN channels play a fundamental role in determining resting membrane potential and regulating synaptic function. Here, we investigated the involvement of HCN channels in basal synaptic transmission and long-term depression (LTD) at the Schaffer collateral-CA1 synapse. Bath application of the HCN channel blocker ZD7288 (10 microM) caused a significant increase in synaptic transmission that was due to an enhancement in AMPA receptor-mediated excitatory postsynaptic potentials. This enhancement was accompanied by a significant decrease in the paired-pulse ratio (PPR), suggesting a presynaptic mechanism. Experiments with the irreversible use-dependent NMDA receptor blocker MK-801 showed that ZD7288 led to an increase in glutamate release probability. LTD induced by brief application of (RS)-3,5-dihydroxyphenylglycine (DHPG, 100 microM, 10 min) was significantly enhanced when HCN channels were blocked by ZD7288 (10 microM) prior to DHPG application. Moreover, the concomitant increase in PPR after DHPG-induced LTD was significantly larger than without ZD7288 bath application. Conversely, ZD7288 application after DHPG washout did not alter DHPG-LTD. A significant enhancement of DHPG-LTD was also observed in HCN1-deficient mice as compared with wild types. However, LTD induced by low-frequency stimulation (LFS) remained unaltered in HCN1-deficient mice, suggesting a differential effect of HCN1 channels on synaptic plasticity constraining DHPG-LTD, but not LFS-LTD.

Mesenchymal Stem Cells Coated with Synthetic Bone-Targeting Polymers Enhance Osteoporotic Bone Fracture Regeneration.

Osteoporosis is a progressive skeletal disease characterized by reduced bone density leading to bone fragility and an elevated risk of bone fractures. In osteoporotic conditions, decrease in bone density happens due to the augmented osteoclastic activity and the reduced number of osteoblast progenitor cells (mesenchymal stem cells, MSCs). We investigated a new method of cell therapy with membrane-engineered MSCs to restore the osteoblast progenitor pool and to inhibit osteoclastic activity in the fractured osteoporotic bones. The primary active sites of the polymer are the N-hydroxysuccinimide and bisphosphonate groups that allow the polymer to covalently bind to the MSCs' plasma membrane, target hydroxyapatite molecules on the bone surface and inhibit osteolysis. The therapeutic utility of the membrane-engineered MSCs was investigated in female rats with induced estrogen-dependent osteoporosis and ulnar fractures. The analysis of the bone density dynamics showed a 27.4% and 21.5% increase in bone density at 4 and 24 weeks after the osteotomy of the ulna in animals that received four transplantations of polymer-modified MSCs. The results of the intravital observations were confirmed by the post-mortem analysis of histological slices of the fracture zones. Therefore, this combined approach that involves polymer and cell transplantation shows promise and warrants further bio-safety and clinical exploration.

High K+-induced contraction requires depolarization-induced Ca2+ release from internal stores in rat gut smooth muscle.

AIM: Depolarization-induced contraction of smooth muscle is thought to be mediated by Ca2+ influx through voltage-gated L-type Ca2+channels. We describe a novel contraction mechanism that is independent of Ca2+ entry. METHODS: Pharmacological experiments were carried out on isolated rat gut longitudinal smooth muscle preparations, measuring isometric contraction strength upon high K+-induced depolarization. RESULTS: Treatment with verapamil, which presumably leads to a conformational change in the channel, completely abolished K+-induced contraction, while residual contraction still occurred when Ca2+ entry was blocked with Cd2+. These results were further confirmed by measuring intracellular Ca2+ transients using Fura-2. Co-application of Cd2+ and the ryanodine receptor blocker DHBP further reduced contraction, albeit incompletely. Additional blockage of either phospholipase C (U 73122) or inositol 1,4,5-trisphophate (IP3)receptors (2-APB) abolished most contractions, while sole application of these blockers and Cd2+ (without parallel ryanodine receptor manipulation) also resulted in incomplete contraction block. CONCLUSION: We conclude that there are parallel mechanisms of depolarization-induced smooth muscle contraction via (a) Ca2+ entry and (b) Ca2+ entry-independent, depolarization-induced Ca2+-release through ryanodine receptors and IP3, with the latter being dependent on phospholipase C activation.

Progress in the Development of Chitosan-Based Biomaterials for Tissue Engineering and Regenerative Medicine.

Over the last few decades, chitosan has become a good candidate for tissue engineering applications. Derived from chitin, chitosan is a unique natural polysaccharide with outstanding properties in line with excellent biodegradability, biocompatibility, and antimicrobial activity. Due to the presence of free amine groups in its backbone chain, chitosan could be further chemically modified to possess additional functional properties useful for the development of different biomaterials in regenerative medicine. In the current review, we will highlight the progress made in the development of chitosan-containing bioscaffolds, such as gels, sponges, films, and fibers, and their possible applications in tissue repair and regeneration, as well as the use of chitosan as a component for drug delivery applications.

Mitochondrial complex IV mutation increases reactive oxygen species production and reduces lifespan in aged mice.

AIM: Mitochondrial DNA (mtDNA) mutations can negatively influence lifespan and organ function. More than 250 pathogenic mtDNA mutations are known, often involving neurological symptoms. Major neurodegenerative diseases share key etiopathogenetic components ie mtDNA mutations, mitochondrial dysfunction and oxidative stress. METHODS: Here, we characterized a conplastic mouse strain (C57BL/6 J-mtNOD) carrying an electron transport chain complex IV mutation that leads to an altered cytochrome c oxidase subunit III. Since this mouse also harbours adenine insertions in the mitochondrial tRNA for arginine, we chose the C57BL/6 J-mtMRL as control strain which also carries a heteroplasmic stretch of adenine repetitions in this tRNA isoform. RESULTS: Using MitoSOX fluorescence, we observed an elevated mitochondrial superoxide production and a reduced gene expression of superoxide dismutase 2 in the 24-month-old mtNOD mouse as compared to control. Together with the decreased expression of the fission-relevant gene Fis1, these data confirmed that the ageing mtNOD mouse had a mitochondrial dysfunctional phenotype. On the functional level, we could not detect significant differences in synaptic long-term potentiation, but found a markedly poor physical constitution to perform the Morris water maze task at the age of 24 months. Moreover, the median lifespan of mtNOD mice was significantly shorter than of control animals. CONCLUSION: Our findings demonstrate that a complex IV mutation leads to mitochondrial dysfunction that translates into survival.

Beta-amyloid peptide stimulates endozepine release in cultured rat astrocytes through activation of N-formyl peptide receptors.

Astroglial cells synthesize and release endozepines, a family of neuropeptides derived from diazepam-binding inhibitor (DBI). The authors have recently shown that beta-amyloid peptide (Abeta) stimulates DBI gene expression and endozepine release. The purpose of this study was to determine the mechanism of action of Abeta in cultured rat astrocytes. Abeta(25-35) and the N-formyl peptide receptor (FPR) agonist N-formyl-Met-Leu-Phe (fMLF) increased the secretion of endozepines in a dose-dependent manner with EC(50) value of approximately 2 microM. The stimulatory effects of Abeta(25-35) and the FPR agonists fMLF and N-formyl-Met-Met-Met (fMMM) on endozepine release were abrogated by the FPR antagonist N-t-Boc-Phe-Leu-Phe-Leu-Phe. In contrast, Abeta(25-35) increased DBI mRNA expression through a FPR-independent mechanism. Abeta(25-35) induced a transient stimulation of cAMP formation and a sustained activation of polyphosphoinositide turnover. The stimulatory effect of Abeta(25-35) on endozepine release was blocked by the adenylyl cyclase inhibitor somatostatin, the protein kinase A (PKA) inhibitor H89, the phospholipase C inhibitor U73122, the protein kinase C (PKC) inhibitor chelerythrine and the ATP binding cassette transporter blocker glyburide. Taken together, these data demonstrate for the first time that Abeta(25-35) stimulates endozepine release from rat astrocytes through a FPR receptor positively coupled to PKA and PKC.

Bidirectional shift of group III metabotropic glutamate receptor-mediated synaptic depression in the epileptic hippocampus.

A common function of group III metabotropic glutamate receptors (mGluRs) located at the presynaptic site of a glutamatergic synapse is synaptic depression. Here, we studied synaptic depression mediated by group III mGluR activation at Schaffer collateral-CA1 (SC-CA1) synapses and associational-commissural-CA3 (AC-CA3) synapses by recording field excitatory postsynaptic potentials in the in vitro brain slice preparation. In order to gauge the impact of synaptic depression in chronically epileptic tissue, we compared rats after pilocarpine-induced status epilepticus (post-SE) with control animals. We observed that synaptic transmission at control AC-CA3 synapses was sensitive to the group III mGluR agonist L-AP4 (10µM), while there was no effect of this compound at SC-CA1 synapses in the same tissue. In contrast, synaptic depression at AC-CA3 synapses by L-AP4 was lost in chronically epileptic tissue, and we found a significant synaptic depression at SC-CA1 synapses in post-SE tissue by L-AP4 and by the mGluR8-selective agonist DCPG. The depression by L-AP4 and DCPG in CA1 was also demonstrated in immature control tissue suggesting developmental down-regulation of mGluR8 at this synapse as well as re-appearance of this isoform under pathological conditions. Quantitative real-time RT-PCR was used to identify mGluR isoforms and to assess their transcriptional changes in post-SE tissue. These analyses revealed down-regulation of mGluR4 and mGluR6 at AC-CA3 and up-regulation of mGluR8 at SC-CA1 synapses. We conclude that group III mGluR-mediated synaptic depression is differentially altered in chronically epileptic tissue by a bidirectional shift of the transcriptional level.

Eag1 K+ Channel: Endogenous Regulation and Functions in Nervous System.

Ether-à-go-go1 (Eag1, Kv10.1, KCNH1) K+ channel is a member of the voltage-gated K+ channel family mainly distributed in the central nervous system and cancer cells. Like other types of voltage-gated K+ channels, the EAG1 channels are regulated by a variety of endogenous signals including reactive oxygen species, rendering the EAG1 to be in the redox-regulated ion channel family. The role of EAG1 channels in tumor development and its therapeutic significance have been well established. Meanwhile, the importance of hEAG1 channels in the nervous system is now increasingly appreciated. The present review will focus on the recent progress on the channel regulation by endogenous signals and the potential functions of EAG1 channels in normal neuronal signaling as well as neurological diseases.

Power of PTEN/AKT: Molecular switch between tumor suppressors and oncogenes.

An increasing amount of evidence has shown that tumor suppressors can become oncogenes, or vice versa, but the mechanism behind this is unclear. Recent findings have suggested that phosphatase and tensin homolog (PTEN) is one of the powerful switches for the conversion between tumor suppressors and oncogenes. PTEN regulates a number of cellular processes, including cell death and proliferation, through the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Furthermore, a number of studies have suggested that PTEN deletions may alter various functions of certain tumor suppressor and oncogenic proteins. The aim of the present review was to analyze specific cases driven by PTEN loss/AKT activation, including aberrant signaling pathways and novel drug targets for clinical application in personalized medicine. The findings illustrate how PTEN loss and/or AKT activation switches MDM2-dependent p53 downregulation, and induces conversion between oncogene and tumor suppressor in enhancer of zeste homolog 2, BTB domain-containing 7A, alternative reading frame 2, p27 and breast cancer 1, early onset, through multiple mechanisms. This review highlights the genetic basis of complex drug targets and provides insights into the rationale of precision cancer therapy.