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 testedwhether LFS-inducedDP is also altered in pathologicalGluN2B 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 M) 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 M) prior to LFS and observed that DPwas 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 requiredNMDA receptor activation, GluN2B-containingNMDA receptors were not involved in this formof depotentiatio

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 testedwhether LFS-inducedDP is also altered in pathologicalGluN2B 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 M) 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 M) prior to LFS and observed that DPwas 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 requiredNMDA receptor activation, GluN2B-containingNMDA receptors were not involved in this formof depotentiatio

Deep brain stimulation for movement disorder treatment: Exploring frequency-dependent efficacy in a computational network model

A large scale computational model of the basal ganglia (BG) network is proposed to describes movement disorder including deep brain stimulation (DBS). The model of this complex network considers four areas of the basal ganglia network: the subthalamic nucleus (STN) as target area of DBS, globus pallidus, both pars externa and pars interna (GPe-GPi), and the thalamus (THA). Parkinsonian conditions are simulated by assuming reduced dopaminergic input and corresponding pronounced inhibitory or disinhibited projections to GPe and GPi. Macroscopic quantities can be derived which correlate closely to thalamic responses and hence motor programme fidelity. It can be demonstrated that depending on different levels of striatal projections to the GPe and GPi, the dynamics of these macroscopic quantities switch from normal conditions to parkinsonian. Simulating DBS on the STN affects the dynamics of the entire network, increasing the thalamic activity to levels close to normal, while differing from both normal and parkinsonian dynamics. Using the mentioned macroscopic quantities, the model proposes optimal DBS frequency ranges above 130 Hz.Comment: 40 pages, 16 figure

NMDA receptor-dependent metaplasticity by high-frequency magnetic stimulation

High-frequency magnetic stimulation (HFMS) can elicit N-methyl-D-aspartate (NMDA) receptor-dependent long-termpotentiation (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-primingwas diminishedwhen applied in the presence of themetabotropic glutamate receptor antagonists (RS)- -methylserine-O-phosphate (MSOP) and (RS)--methyl-4-carboxyphenylglycine (MCPG).Moreover,whenHFMSwas delivered in the presence of the NMDA receptor-antagonist D-2-amino-5-phosphonovalerate (50 M), 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

NMDA receptor-dependent metaplasticity by high-frequency magnetic stimulation

High-frequency magnetic stimulation (HFMS) can elicit N-methyl-D-aspartate (NMDA) receptor-dependent long-termpotentiation (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-primingwas diminishedwhen applied in the presence of themetabotropic glutamate receptor antagonists (RS)- -methylserine-O-phosphate (MSOP) and (RS)--methyl-4-carboxyphenylglycine (MCPG).Moreover,whenHFMSwas delivered in the presence of the NMDA receptor-antagonist D-2-amino-5-phosphonovalerate (50 M), 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

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

Living Long and Well: Prospects for a Personalized Approach to the Medicine of Ageing.

Research into ageing and its underlying molecular basis enables us to develop and implement targeted interventions to ameliorate or cure its consequences. However, the efficacy of interventions often differs widely between individuals, suggesting that populations should be stratified or even individualized. Large-scale cohort studies in humans, similar systematic 56 studies in model organisms, and detailed investigations into the biology of ageing can provide individual validated biomarkers and mechanisms, leading to recommendations for targeted interventions. Human cohort studies are already ongoing, and can be supplemented by in silico simulations. Systematic studies in animal models are made possible by the use of inbred strains, or genetic reference populations of mice. Combining both, the comprehensive picture of the various determinants of ageing and healthspan can be studied in detail, and an appreciation of the relevance of results from model organisms to humans emerges. The interactions between genotype and environment, particularly the psychosocial environment, are poorly studied in both humans and model organisms, presenting serious challenges to any approach to a personalized medicine of ageing. To increase success of preventive interventions, we argue that there is a pressing need for an individualized evaluation of interventions such as physical exercise, nutrition, nutraceuticals and calorie restriction mimetics as well as psychosocial and environmental factors, separately and in combination. The expected extension of healthspan enables us to refocus healthcare spending on individual prevention starting in late adulthood, and on the brief period of morbidity at very old age

Hyperpolarization-Activated Cyclic Nucleotide-Gated Non-selective (HCN) Ion Channels Regulate Human and Murine Urinary Bladder Contractility

Purpose: Hyperpolarization-activated cyclic nucleotide gated non-selective (HCN) channels have been demonstrated in the urinary bladder in various species. Since they play a major role in governing rhythmic activity in pacemaker cells like in the sinoatrial node, we explored the role of these channels in human and murine detrusor smooth muscle.Methods: In an organ bath, human and murine detrusor smooth muscle specimens were challenged with the HCN channel blocker ZD7288. In human tissue derived from macroscopically tumor-free cancer resections, the urothelium was removed. In addition, HCN1-deficient mice were used to identify the contribution of this particular isoform. Expression of HCN channels in the urinary bladder was analyzed using histological and ultrastructural analyses as well as quantitative reverse transcriptase polymerase chain reaction (RT-PCR).Results: We found that the HCN channel blocker ZD7288 (50 μM) both induced tonic contractions and increased phasic contraction amplitudes in human and murine detrusor specimens. While these responses were not sensitive to tetrodotoxin, they were significantly reduced by the gap junction inhibitor 18β-glycyrrhetic acid suggesting that HCN channels are located within the gap junction-interconnected smooth muscle cell network rather than on efferent nerve fibers. Immunohistochemistry suggested HCN channel expression on smooth muscle tissue, and immunoelectron microscopy confirmed the scattered presence of HCN2 on smooth muscle cell membranes. HCN channels seem to be down-regulated with aging, which is paralleled by an increasing effect of ZD7288 in aging detrusor tissue. Importantly, the anticonvulsant and HCN channel activator lamotrigine relaxed the detrusor which could be reversed by ZD7288.Conclusion: These findings demonstrate that HCN channels are functionally present and localized on smooth muscle cells of the urinary bladder. Given the age-dependent decline of these channels in humans, activation of HCN channels by compounds such as lamotrigine opens up the opportunity to combat detrusor hyperactivity in the elderly by drugs already approved for epilepsy

Inbred mouse strains reveal biomarkers that are pro-longevity, antilongevity or role switching.

Traditionally, biomarkers of aging are classified as either pro-longevity or antilongevity. Using longitudinal data sets from the large-scale inbred mouse strain study at the Jackson Laboratory Nathan Shock Center, we describe a protocol to identify two kinds of biomarkers: those with prognostic implication for lifespan and those with longitudinal evidence. Our protocol also identifies biomarkers for which, at first sight, there is conflicting evidence. Conflict resolution is possible by postulating a role switch. In these cases, high biomarker values are, for example, antilongevity in early life and pro-longevity in later life. Role-switching biomarkers correspond to features that must, for example, be minimized early, but maximized later, for optimal longevity. The clear-cut pro-longevity biomarkers we found reflect anti-inflammatory, anti-immunosenescent or anti-anaemic mechanisms, whereas clear-cut antilongevity biomarkers reflect inflammatory mechanisms. Many highly significant blood biomarkers relate to immune system features, indicating a shift from adaptive to innate processes, whereas most role-switching biomarkers relate to blood serum features and whole-body phenotypes. Our biomarker classification approach is applicable to any combination of longitudinal studies with life expectancy data, and it provides insights beyond a simplified scheme of biomarkers for long or short lifespan