Distinct GABAergic modulation of timing-dependent LTP in CA1 pyramidal neurons along the longitudinal axis of the mouse hippocampus.

Synaptic plasticity in the hippocampus underlies episodic memory formation, with dorsal hippocampus being instrumental for spatial memory whereas ventral hippocampus is crucial for emotional learning. Here, we studied how GABAergic inhibition regulates physiologically relevant low repeat spike timing-dependent LTP (t-LTP) at Schaffer collateral-CA1 synapses along the dorsoventral hippocampal axis. We used two t-LTP protocols relying on only 6 repeats of paired spike-firing in pre- and postsynaptic cells within 10 s that differ in postsynaptic firing patterns. GABAA receptor mechanisms played a greater role in blocking 6× 1:1 t-LTP that recruits single postsynaptic action potentials. 6× 1:4 t-LTP that depends on postsynaptic burst-firing unexpectedly required intact GABAB receptor signaling. The magnitude of both t-LTP-forms decreased along the dorsoventral axis, despite increasing excitability and basal synaptic strength in this direction. This suggests that GABAergic inhibition contributes to the distinct roles of dorsal and ventral hippocampus in memory formation.

Brain-Derived neurotrophic factor and inflammatory biomarkers are unaffected by acute and chronic intermittent hypoxic-hyperoxic exposure in geriatric patients: a randomized controlled trial.

BACKGROUND: Animal and human studies have shown that exposure to hypoxia can increase brain-derived neurotrophic factor (BDNF) protein transcription and reduce systematic inflammatory cytokine response. Therefore, the aim of this study was to investigate the acute and chronic effects of intermittent hypoxic-hyperoxic exposure (IHHE) prior to aerobic exercise on BDNF, interleukin-6 (IL-6), and C-reactive protein (CRP) blood levels in geriatric patients. PATIENTS AND METHODS: Twenty-five geriatric patients (83.1 ± 5.0 yrs, 71.1 ± 10.0 kg, 1.8 ± 0.9 m) participated in a placebo-controlled, single-blinded trial and were randomly assigned to either an intervention (IG) or control group (CG) performing an aerobic cycling training (17 sessions, 20 min·session-1, 3 sessions·week-1). Prior to aerobic cycling exercise, the IG was additionally exposed to IHHE for 30 min, whereas the CG received continuous normoxic air. Blood samples were taken immediately before (pre-exercise) and 10 min (post-exercise) after the first session as well as 48 h (post-training) after the last session to determine serum (BDNFS) and plasma BDNF (BDNFP), IL-6, and CRP levels. Intervention effects were analyzed using a 2 x 2 analysis of covariance with repeated measures. Results were interpreted based on effect sizes with a medium effect considered as meaningful (ηp2 ≥ 0.06, d ≥ 0.5). RESULTS: CRP was moderately higher (d = 0.51) in the CG compared to the IG at baseline. IHHE had no acute effect on BDNFS (ηp2 = 0.01), BDNFP (ηp2 < 0.01), BDNF serum/plasma-ratio (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 = 0.04). After the 6-week intervention, an interaction was found for BDNF serum/plasma-ratio (ηp2 = 0.06) but not for BDNFS (ηp2 = 0.04), BDNFP (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 < 0.01). BDNF serum/plasma-ratio increased from pre-exercise to post-training (d = 0.67) in the CG compared to the IG (d = 0.51). A main effect of time was found for BDNFP (ηp2 = 0.09) but not for BDNFS (ηp2 = 0.02). Within-group post-hoc analyses revealed a training-related reduction in BDNFP in the IG and CG by 46.1% (d = 0.73) and 24.7% (d = 0.57), respectively. CONCLUSION: The addition of 30 min IHHE prior to 20 min aerobic cycling seems not to be effective to increase BDNFS and BDNFP or to reduce IL-6 and CRP levels in geriatric patients after a 6-week intervention.The study was retrospectively registered at drks.de (DRKS-ID: DRKS00025130).

A delay in vesicle endocytosis by a C-terminal fragment of N-cadherin enhances Aß synaptotoxicity.

Synaptotoxic Aß oligomers are thought to play a major role in the early pathology of Alzheimer´s disease (AD). However, the molecular mechanisms involved in Aß-induced synaptic dysfunction and synapse damage remain largely unclear. Previously, Aß synaptotoxicity has been reported to be enhanced by increased levels of a C-terminal fragment of the synaptic adhesion molecule N-cadherin that is generated by proteolytic shedding of the extracellular domains [1]. To address the molecular mechanisms involved in this process, we have now studied the functional synaptic changes induced by C-terminal fragments (CTF1) of synaptic adhesion proteins. We used synaptophysin-pHluorin (SypHy) fluorescence imaging to monitor synaptic vesicle exo- and endocytosis in cultures of mouse cortical neurons. We increased the levels of C-terminal fragments of synaptic adhesion proteins by pharmacologically inhibiting γ-secretase, which further degrades CTF1 fragments. We found that this intervention caused a delay in synaptic vesicle endocytosis. A similar effect was induced by overexpression of N-cadherin CTF1, but not by overexpression of Neurexin3ß CTF1. Based on these observations, we further studied whether directly modulating synaptic vesicle endocytosis enhances Aß synaptotoxicity. We pharmacologically induced a delayed synaptic vesicle endocytosis by a low concentration of the endocytosis inhibitor dynasore. This treatment enhanced synaptoxicity of Aß oligomers as indicated by a reduced frequency of miniature postsynaptic currents. In conclusion, we propose that delayed endocytosis results in prolonged exposure of synaptic vesicle membranes to the extracellular space, thus enabling enhanced vesicle membrane binding of Aß oligomers. This might in turn promote the endocytic uptake of toxic Aß oligomers and might thus play an important role in intracellular Aß-mediated synaptotoxicity in AD.

Flow down gradients: the problem of pressure in this physiology core concept.

The core concepts of physiology, as first published in this journal in 2011, not only provide a noteworthy teaching approach but also encourage reflection on the fundamentals of physiology. Unfortunately, a fundamental flaw has crept into the core concept of flow down gradients. Fluids do not generally flow from high to low pressure, as claimed, but only because of a specific pressure difference, that is, the perfusion pressure. This is related to a problem that is widespread in physiology, from which even the core concepts are not free, namely, the description of mean arterial pressure (MAP) solely by means of Ohm's law of circulation, although this law actually describes perfusion pressure. Both pressures can be numerically approximately equal in the physiological case, but conceptually they remain different in principle. We solved this problem using the extended Bernoulli equation (a combination of Ohm's law and the simple Bernoulli equation). Thereafter, MAP depends on the following pressure components, all of which are essential for a basic understanding of circulation: perfusion, central venous, gravitational, and dynamic pressures. These pressures also have great pathophysiological and clinical importance, which we exemplify here. Toward the end of this article, we provide recommendations that should be considered in teaching, whether it is a beginner or advanced course. We address physiology teachers who are open to critical constructive improvements in their teaching, especially in hemodynamics. In particular, we encourage the authors of the flow down gradients core concept to improve and refine its "unpacking."NEW & NOTEWORTHY This article addresses physiology teachers and in particular the authors of the core concept of flow down gradients. Using mean arterial pressure (MAP) as an example, we demonstrate the conceptual problems of pressure that must be considered in teaching to prevent misconceptions. Even in beginner courses, the acting pressures should be clearly distinguished (e.g., MAP vs. perfusion pressure). In advanced courses, we recommend a mathematical description of pressure (Ohm's law and Bernoulli's equation).

Repurposing drugs against Alzheimer's disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?

Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models and in humans suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals or in elderly humans before onset of disease symptoms. However, a pharmacological treatment that can reverse memory deficits in AD patients was thus far not identified. Importantly, AD disease-related dysfunctions have increasingly been associated with neuro-inflammatory mechanisms and searching for anti-inflammatory medication to treat AD seems promising. Like for other diseases, repurposing of FDA-approved drugs for treatment of AD is an ideally suited strategy to reduce the time to bring such medication into clinical practice. Of note, the sphingosine-1-phosphate analogue fingolimod (FTY720) was FDA-approved in 2010 for treatment of multiple sclerosis patients. It binds to the five different isoforms of Sphingosine-1-phosphate receptors (S1PRs) that are widely distributed across human organs. Interestingly, recent studies in five different mouse models of AD suggest that FTY720 treatment, even when starting after onset of AD symptoms, can reverse synaptic deficits and memory dysfunction in these AD mouse models. Furthermore, a very recent multi-omics study identified mutations in the sphingosine/ceramide pathway as a risk factor for sporadic AD, suggesting S1PRs as promising drug target in AD patients. Therefore, progressing with FDA-approved S1PR modulators into human clinical trials might pave the way for these potential disease modifying anti-AD drugs.

Proteomics of the dentate gyrus reveals semantic dementia specific molecular pathology.

Semantic dementia (SD) is a clinical subtype of frontotemporal dementia consistent with the neuropathological diagnosis frontotemporal lobar degeneration (FTLD) TDP type C, with characteristic round TDP-43 protein inclusions in the dentate gyrus. Despite this striking clinicopathological concordance, the pathogenic mechanisms are largely unexplained forestalling the development of targeted therapeutics. To address this, we carried out laser capture microdissection of the dentate gyrus of 15 SD patients and 17 non-demented controls, and assessed relative protein abundance changes by label-free quantitative mass spectrometry. To identify SD specific proteins, we compared our results to eight other FTLD and Alzheimer's disease (AD) proteomic datasets of cortical brain tissue, parallel with functional enrichment analyses and protein-protein interactions (PPI). Of the total 5,354 quantified proteins, 151 showed differential abundance in SD patients (adjusted P-value < 0.01). Seventy-nine proteins were considered potentially SD specific as these were not detected, or demonstrated insignificant or opposite change in FTLD/AD. Functional enrichment indicated an overrepresentation of pathways related to the immune response, metabolic processes, and cell-junction assembly. PPI analysis highlighted a cluster of interacting proteins associated with adherens junction and cadherin binding, the cadherin-catenin complex. Multiple proteins in this complex showed significant upregulation in SD, including ß-catenin (CTNNB1), γ-catenin (JUP), and N-cadherin (CDH2), which were not observed in other neurodegenerative proteomic studies, and hence may resemble SD specific involvement. A trend of upregulation of all three proteins was observed by immunoblotting of whole hippocampus tissue, albeit only significant for N-cadherin. In summary, we discovered a specific increase of cell adhesion proteins in SD constituting the cadherin-catenin complex at the synaptic membrane, essential for synaptic signaling. Although further investigation and validation are warranted, we anticipate that these findings will help unravel the disease processes underlying SD.

Brain-derived neurotrophic factor expression in serotonergic neurons improves stress resilience and promotes adult hippocampal neurogenesis.

The neurotrophin brain-derived neurotrophic factor (BDNF) stimulates adult neurogenesis, but also influences structural plasticity and function of serotonergic neurons. Both, BDNF/TrkB signaling and the serotonergic system modulate behavioral responses to stress and can lead to pathological states when dysregulated. The two systems have been shown to mediate the therapeutic effect of antidepressant drugs and to regulate hippocampal neurogenesis. To elucidate the interplay of both systems at cellular and behavioral levels, we generated a transgenic mouse line that overexpresses BDNF in serotonergic neurons in an inducible manner. Besides displaying enhanced hippocampus-dependent contextual learning, transgenic mice were less affected by chronic social defeat stress (CSDS) compared to wild-type animals. In parallel, we observed enhanced serotonergic axonal sprouting in the dentate gyrus and increased neural stem/progenitor cell proliferation, which was uniformly distributed along the dorsoventral axis of the hippocampus. In the forced swim test, BDNF-overexpressing mice behaved similarly as wild-type mice treated with the antidepressant fluoxetine. Our data suggest that BDNF released from serotonergic projections exerts this effect partly by enhancing adult neurogenesis. Furthermore, independently of the genotype, enhanced neurogenesis positively correlated with the social interaction time after the CSDS, a measure for stress resilience.

Structural and functional brain alterations in patients with myasthenia gravis.

Myasthenia gravis is an autoimmune disease affecting neuromuscular transmission and causing skeletal muscle weakness. Additionally, systemic inflammation, cognitive deficits and autonomic dysfunction have been described. However, little is known about myasthenia gravis-related reorganization of the brain. In this study, we thus investigated the structural and functional brain changes in myasthenia gravis patients. Eleven myasthenia gravis patients (age: 70.64 ± 9.27; 11 males) were compared to age-, sex- and education-matched healthy controls (age: 70.18 ± 8.98; 11 males). Most of the patients (n = 10, 0.91%) received cholinesterase inhibitors. Structural brain changes were determined by applying voxel-based morphometry using high-resolution T1-weighted sequences. Functional brain changes were assessed with a neuropsychological test battery (including attention, memory and executive functions), a spatial orientation task and brain-derived neurotrophic factor blood levels. Myasthenia gravis patients showed significant grey matter volume reductions in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus. Furthermore, myasthenia gravis patients showed significantly lower performance in executive functions, working memory (Spatial Span, P = 0.034, d = 1.466), verbal episodic memory (P = 0.003, d = 1.468) and somatosensory-related spatial orientation (Triangle Completion Test, P = 0.003, d = 1.200). Additionally, serum brain-derived neurotrophic factor levels were significantly higher in myasthenia gravis patients (P = 0.001, d = 2.040). Our results indicate that myasthenia gravis is associated with structural and functional brain alterations. Especially the grey matter volume changes in the cingulate gyrus and the inferior parietal lobe could be associated with cognitive deficits in memory and executive functions. Furthermore, deficits in somatosensory-related spatial orientation could be associated with the lower volumes in the inferior parietal lobe. Future research is needed to replicate these findings independently in a larger sample and to investigate the underlying mechanisms in more detail.

Membrane electrical properties of mouse hippocampal CA1 pyramidal neurons during strong inputs.

In this work, we highlight an electrophysiological feature often observed in recordings from mouse CA1 pyramidal cells that has so far been ignored by experimentalists and modelers. It consists of a large and dynamic increase in the depolarization baseline (i.e., the minimum value of the membrane potential between successive action potentials during a sustained input) in response to strong somatic current injections. Such an increase can directly affect neurotransmitter release properties and, more generally, the efficacy of synaptic transmission. However, it cannot be explained by any currently available conductance-based computational model. Here we present a model addressing this issue, demonstrating that experimental recordings can be reproduced by assuming that an input current modifies, in a time-dependent manner, the electrical and permeability properties of the neuron membrane by shifting the ionic reversal potentials and channel kinetics. For this reason, we propose that any detailed model of ion channel kinetics for neurons exhibiting this characteristic should be adapted to correctly represent the response and the synaptic integration process during strong and sustained inputs.

ProBDNF Dependence of LTD and Fear Extinction Learning in the Amygdala of Adult Mice.

Neurotrophins are secreted proteins that control survival, differentiation, and synaptic plasticity. While mature neurotrophins regulate these functions via tyrosine kinase signaling (Trk), uncleaved pro-neurotrophins bind preferentially to the p75 neurotrophin receptor (p75NTR) and often exert opposite effects to those of mature neurotrophins. In the amygdala, brain-derived neurotrophic factor (BDNF) enables long-term potentiation as well as fear and fear extinction learning. In the present study, we focused on the impact of mature BDNF and proBDNF signaling on long-term depression (LTD) in the lateral amygdala (LA). Hence, we conducted extracellular field potential recordings in an in vitro slice preparation and recorded LTD in cortical and thalamic afferents to the LA. LTD was unchanged by acute block of BDNF/TrkB signaling. In contrast, LTD was inhibited by blocking p75NTR signaling, by disinhibition of the proteolytic cleavage of proBDNF into mature BDNF, and by preincubation with a function-blocking anti-proBDNF antibody. Since LTD-like processes in the amygdala are supposed to be related to fear extinction learning, we locally inhibited p75NTR signaling in the amygdala during or after fear extinction training, resulting in impaired fear extinction memory. Overall, these results suggest that in the amygdala proBDNF/p75NTR signaling plays a pivotal role in LTD and fear extinction learning.

Calcium-Permeable AMPA Receptors Mediate Timing-Dependent LTP Elicited by Low Repeat Coincident Pre- and Postsynaptic Activity at Schaffer Collateral-CA1 Synapses.

High-frequency stimulation induced long-term potentiation (LTP) and low-frequency stimulation induced LTD are considered as cellular models of memory formation. Interestingly, spike timing-dependent plasticity (STDP) can induce equally robust timing-dependent LTP (t-LTP) and t-LTD in response to low frequency repeats of coincident action potential (AP) firing in presynaptic and postsynaptic cells. Commonly, STDP paradigms relying on 25-100 repeats of coincident AP firing are used to elicit t-LTP or t-LTD, but the minimum number of repeats required for successful STDP is barely explored. However, systematic investigation of physiologically relevant low repeat STDP paradigms is of utmost importance to explain learning mechanisms in vivo. Here, we examined low repeat STDP at Schaffer collateral-CA1 synapses by pairing one presynaptic AP with either one postsynaptic AP (1:1 t-LTP), or a burst of 4 APs (1:4 t-LTP) and found 3-6 repeats to be sufficient to elicit t-LTP. 6× 1:1 t-LTP required postsynaptic Ca2+ influx via NMDARs and L-type VGCCs and was mediated by increased presynaptic glutamate release. In contrast, 1:4 t-LTP depended on postsynaptic metabotropic GluRs and ryanodine receptor signaling and was mediated by postsynaptic insertion of AMPA receptors. Unexpectedly, both 6× t-LTP variants were strictly dependent on activation of postsynaptic Ca2+-permeable AMPARs but were differentially regulated by dopamine receptor signaling. Our data show that synaptic changes induced by only 3-6 repeats of mild STDP stimulation occurring in ≤10 s can take place on time scales observed also during single trial learning.

Comparison of the effects of open vs. closed skill exercise on the acute and chronic BDNF, IGF-1 and IL-6 response in older healthy adults.

BACKGROUND: Accumulating evidence shows that physical exercise has a positive effect on the release of neurotrophic factors and myokines. However, evidence regarding the optimal type of physical exercise for these release is still lacking. The aim of this study was to assess the acute and chronic effects of open-skill exercise (OSE) compared to closed-skill exercise (CSE) on serum and plasma levels of brain derived neurotrophic factor (BDNFS, BDNFP), and serum levels of insulin like growth factor 1 (IGF-1), and interleukin 6 (IL-6) in healthy older adults. METHODS: To investigate acute effects, thirty-eight participants were randomly assigned to either an intervention (badminton (aOSE) and bicycling (aCSE), n = 24, 65.83 ± 5.98 years) or control group (reading (CG), n = 14, 67.07 ± 2.37 years). Blood samples were taken immediately before and 5 min after each condition. During each condition, heart rate was monitored. The mean heart rate of aOSE and aCSE were equivalent (65 ± 5% of heart rate reserve). In a subsequent 12-week training-intervention, twenty-two participants were randomly assigned to either a sport-games (cOSE, n = 6, 64.50 ± 6.32) or a strength-endurance training (cCSE, n = 9, 64.89 ± 3.51) group to assess for chronic effects. Training intensity for both groups was adjusted to a subjective perceived exertion using the CR-10 scale (value 7). Blood samples were taken within one day after the training-intervention. RESULTS: BDNFS, BDNFP, IGF-1, and IL-6 levels increased after a single exercise session of 30 min. After 12 weeks of training BDNFS and IL-6 levels were elevated, whereas IGF-1 levels were reduced in both groups. However, only in the cOSE group these changes were significant. We could not find any significant differences between the exercise types. CONCLUSION: Our results indicate that both exercise types are efficient to acutely increase BDNFS, BDNFP, IGF-1 and IL-6 serum levels in healthy older adults. Additionally, our results tend to support that OSE is more effective for improving basal BDNFS levels after 12 weeks of training.

BDNF haploinsufficiency induces behavioral endophenotypes of schizophrenia in male mice that are rescued by enriched environment.

Brain-derived neurotrophic factor (BDNF) is implicated in a number of processes that are crucial for healthy functioning of the brain. Schizophrenia is associated with low BDNF levels in the brain and blood, however, not much is known about BDNF's role in the different symptoms of schizophrenia. Here, we used BDNF-haploinsufficient (BDNF+/-) mice to investigate the role of BDNF in different mouse behavioral endophenotypes of schizophrenia. Furthermore, we assessed if an enriched environment can prevent the observed changes. In this study, male mature adult wild-type and BDNF+/- mice were tested in mouse paradigms for cognitive flexibility (attentional set shifting), sensorimotor gating (prepulse inhibition), and associative emotional learning (safety and fear conditioning). Before these tests, half of the mice had a 2-month exposure to an enriched environment, including running wheels. After the tests, BDNF brain levels were quantified. BDNF+/- mice had general deficits in the attentional set-shifting task, increased startle magnitudes, and prepulse inhibition deficits. Contextual fear learning was not affected but safety learning was absent. Enriched environment housing completely prevented the observed behavioral deficits in BDNF+/- mice. Notably, the behavioral performance of the mice was negatively correlated with BDNF protein levels. These novel findings strongly suggest that decreased BDNF levels are associated with several behavioral endophenotypes of schizophrenia. Furthermore, an enriched environment increases BDNF protein to wild-type levels and is thereby able to rescue these behavioral endophenotypes.

Long-term depression at hippocampal mossy fiber-CA3 synapses involves BDNF but is not mediated by p75NTR signaling.

BDNF plays a crucial role in the regulation of synaptic plasticity. It is synthesized as a precursor (proBDNF) that can be proteolytically cleaved to mature BDNF (mBDNF). Previous studies revealed a bidirectional mode of BDNF actions, where long-term potentiation (LTP) was mediated by mBDNF through tropomyosin related kinase (Trk) B receptors whereas long-term depression (LTD) depended on proBDNF/p75 neurotrophin receptor (p75NTR) signaling. While most experimental evidence for this BDNF dependence of synaptic plasticity in the hippocampus was derived from Schaffer collateral (SC)-CA1 synapses, much less is known about the mechanisms of synaptic plasticity, in particular LTD, at hippocampal mossy fiber (MF) synapses onto CA3 neurons. Since proBDNF and mBDNF are expressed most abundantly at MF-CA3 synapses in the rodent brain and we had shown previously that MF-LTP depends on mBDNF/TrkB signaling, we now explored the role of proBDNF/p75NTR signaling in MF-LTD. Our results show that neither acute nor chronic inhibition of p75NTR signaling impairs MF-LTD, while short-term plasticity, in particular paired-pulse facilitation, at MF-CA3 synapses is affected by a lack of functional p75NTR signaling. Furthermore, MF-CA3 synapses showed normal LTD upon acute inhibition of TrkB receptor signaling. Nonetheless, acute inhibition of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of both intracellular and extracellular proBDNF cleavage, impaired MF-LTD. This seems to indicate that LTD at MF-CA3 synapses involves BDNF, however, MF-LTD does not depend on p75NTRs. Altogether, our experiments demonstrate that p75NTR signaling is not warranted for all glutamatergic synapses but rather needs to be checked separately for every synaptic connection.

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aß Plaques.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-ß (Aß) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aß plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aß plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aß plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aß plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.

Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model.

Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of Aß accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.

The physiology of regulated BDNF release.

The neurotrophic factor BDNF is an important regulator for the development of brain circuits, for synaptic and neuronal network plasticity, as well as for neuroregeneration and neuroprotection. Up- and downregulations of BDNF levels in human blood and tissue are associated with, e.g., neurodegenerative, neurological, or even cardiovascular diseases. The changes in BDNF concentration are caused by altered dynamics in BDNF expression and release. To understand the relevance of major variations of BDNF levels, detailed knowledge regarding physiological and pathophysiological stimuli affecting intra- and extracellular BDNF concentration is important. Most work addressing the molecular and cellular regulation of BDNF expression and release have been performed in neuronal preparations. Therefore, this review will summarize the stimuli inducing release of BDNF, as well as molecular mechanisms regulating the efficacy of BDNF release, with a focus on cells originating from the brain. Further, we will discuss the current knowledge about the distinct stimuli eliciting regulated release of BDNF under physiological conditions.

Neurotrophin signalling in amygdala-dependent cued fear learning.

The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced.