Impairments of hippocampal synaptic plasticity induced by aggregated beta-amyloid (25-35) are dependent on stimulation-protocol and genetic background

The aggregation of beta-amyloid to plaques in the brain is one of the hallmarks of Alzheimer disease (AD). Numerous studies have tried to elucidate to what degree amyloid peptides play a role in the neurodegenerative developments seen in AD. While most studies report an effect of amyloid on neural activity and cognitive abilities of rodents, there have been many inconsistencies in the results. This study investigated to what degree the different genetic backgrounds affect the outcome of beta-amyloid fragment (25-35) on synaptic plasticity in vivo in the rat hippocampus. Two strains, Wistar and Lister hooded rats, were tested. In addition, the effects of a strong (600 stimuli) and a weak stimulation protocol (100 stimuli) on impairments of LTP were analysed. Furthermore, since the state of amyloid aggregation appears to play a role in the induction of toxic processes, it was tested by dual polarisation interferometry to what degree and at what speed beta-amyloid (25-35) can aggregate in vitro. It was found that 100 nmol beta-amyloid (25-35) injected icv did impair LTP in Wistar rats when using the weak but not the strong stimulation protocol (P <0.001). One-hundred nano mole of the reverse sequence amyloid (35-25) had no effect. LTP in Lister Hooded rats was not impaired by amyloid at any stimulation protocol. The aggregation studies showed that amyloid (25-35) aggregated within hours, while amyloid (35-25) did not. These results show that the genetic background and the stimulation protocol are important variables that greatly influence the experimental outcome. The fact that amyloid (25-35) aggregated quickly and showed neurophysiological effects, while amyloid (35-25) did not aggregate and did not show any effects indicates that the state of aggregation plays an important role in the physiological effects.

An orally available compound prevents deficits in memory caused by the Alzheimer amyloid-B oligomers.

Despite progress in defining a pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, orally bioavailable compounds that prevent its effects on hippocampal synaptic plasticity and cognitive function have not yet emerged. A particularly attractive therapeutic strategy is to selectively neutralize small, soluble Abeta oligomers that have recently been shown to mediate synaptic dysfunction. METHODS: Using electrophysiological, biochemical, and behavioral assays, we studied how scyllo-inositol (AZD-103; molecular weight, 180) neutralizes the acutely toxic effects of Abeta on synaptic function and memory recall. RESULTS: Scyllo-inositol, but not its stereoisomer, chiro-inositol, dose-dependently rescued long-term potentiation in mouse hippocampus from the inhibitory effects of soluble oligomers of cell-derived human Abeta. Cerebroventricular injection into rats of the soluble Abeta oligomers interfered with learned performance on a complex lever-pressing task, but administration of scyllo-inositol via the drinking water fully prevented oligomer-induced errors. INTERPRETATION: A small, orally available natural product penetrates into the brain in vivo to rescue the memory impairment produced by soluble Abeta oligomers through a mechanism that restores hippocampal synaptic plasticity.

A heterosynaptic learning rule for neural networks

In this article we intoduce a novel stochastic Hebb-like learning rule for neural networks that is neurobiologically motivated. This learning rule combines features of unsupervised (Hebbian) and supervised (reinforcement) learning and is stochastic with respect to the selection of the time points when a synapse is modified. Moreover, the learning rule does not only affect the synapse between pre- and postsynaptic neuron, which is called homosynaptic plasticity, but effects also further remote synapses of the pre-and postsynaptic neuron. This more complex form of synaptic plasticity has recently come under investigations in neurobiology and is called heterosynaptic plasticity. We demonstrate that this learning rule is useful in training neural networks by learning parity functions including the exclusive-or (XOR) mapping in a multilayer feed-forward network. We find, that our stochastic learning rule works well, even in the presence of noise. Importantly, the mean leaxning time increases with the number of patterns to be learned polynomially, indicating efficient learning.

mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning

Highly selective positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have emerged as a potential approach to treat positive symptoms associated with schizophrenia. mGluR5 plays an important role in both long-term potentiation (LTP) and long-term depression (LTD), suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. However, if mGluR5 PAMs shift the balance of LTP and LTD or induce a state in which afferent activity induces lasting changes in synaptic function that are not appropriate for a given pattern of activity, this could disrupt rather than enhance cognitive function. We determined the effect of selective mGluR5 PAMs on the induction of LTP and LTD at the Schaffer collateral-CA1 synapse in the hippocampus. mGluR5-selective PAMs significantly enhanced threshold theta-burst stimulation (TBS)-induced LTP. In addition, mGluR5 PAMs enhanced both DHPG-induced LTD and LTD induced by the delivery of paired-pulse low-frequency stimulation. Selective potentiation of mGluR5 had no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD and supports the hypothesis that the activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, two systemically active mGluR5 PAMs enhanced performance in the Morris water maze, a measure of hippocampus-dependent spatial learning. Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner shows a unique action on synaptic plasticity that may provide a novel approach for the treatment of impaired cognitive function. Neuropsychopharmacology (2009) 34, 2057-2071; doi:10.1038/npp.2009.30; published online 18 March 2009

Orally bioavailable small molecule drug protects memory in Alzheimer's disease models

Oligomers of beta-amyloid (Aß) are implicated in the early memory impairment seen in Alzheimer's disease before to the onset of discernable neurodegeneration. Here, the capacity of a novel orally bioavailable, central nervous system-penetrating small molecule 5-aryloxypyrimidine, SEN1500, to prevent cell-derived (7PA2 [conditioned medium] CM) Aß-induced deficits in synaptic plasticity and learned behavior was assessed. Biochemically, SEN1500 bound to Aß monomer and oligomers, produced a reduction in thioflavin-T fluorescence, and protected a neuronal cell line and primary cortical neurons exposed to synthetic soluble oligomeric Aß1-42. Electrophysiologically, SEN1500 alleviated the in vitro depression of long-term potentiation induced by both synthetic Aß1-42 and 7PA2 CM, and alleviated the in vivo depression of long-term potentiation induced by 7PA2 CM, after systemic administration. Behaviorally, oral administration of SEN1500 significantly reduced memory-related deficits in operant responding induced after intracerebroventricular injection of 7PA2 CM. SEN1500 reduced cytotoxicity, acute synaptotoxicity, and behavioral deterioration after in vitro and in vivo exposure to synthetic Aß and 7PA2 CM, and shows promise for development as a clinically viable disease-modifying Alzheimer's disease treatment. © 2013 Elsevier Inc.

Recapitulation of embryological programmes in renal fibrosis - The importance of epithelial cell plasticity and developmental genes

Chronic fibrosis represents the final common pathway in progressive renal disease. Myofibroblasts deposit the constituents of renal scar, thus crippling renal function. It has recently emerged that an important source of these pivotal effector cells is the injured renal epithelium. This review concentrates on the process of epithelial-mesenchymal transition (EMT) and its regulation. The role of the developmental gene, gremlin, which is reactivated in adult renal disease, is the subject of particular focus. This member of the cysteine knot protein superfamily is critical to the process of nephrogenesis but quiescent in normal adult kidney. There is increasing evidence that gremlin expression reactivates in diabetic nephropathy, and in the diseased fibrotic kidney per se. Known to antagonize members of the bone morphogenic protein (BMP) family, gremlin may also act downstream of TGF-beta in induction of EMT. An increased understanding of the extracellular modulation of EMT and, in particular, of the gremlin-BMP axis may result in strategies that can halt or reverse the devastating progression of chronic renal fibrosis. Copyright (c) 2006 S. Karger AG, Basel.

An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.

Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M₄ allosteric potentiators. VU10010, the lead compound, potentiates the M₄ response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M₄ with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M₄ knockout mice. Selective regulation of excitatory transmission by M₄ suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.

Behavioral plasticity allows short-term adjustment to a novel environment

Many species are currently experiencing anthropogenically driven environmental changes. Among these changes, increasing noise levels are specifically a problem for species relying on acoustic communication. Recent evidence suggests that some species adjust their acoustic signals to man-made noise. However, it is unknown whether these changes occur through short-term and reversible adjustments by behavioral plasticity or through long-term adaptations by evolutionary change. Using behavioral observations and playback experiments, we show that male reed buntings (Emberiza schoeniclus) adjusted their songs immediately, singing at a higher minimum frequency and at a lower rate when noise levels were high. Our data showed that these changes in singing behavior were short-term adjustments of signal characteristics resulting from behavioral plasticity, rather than a long-term adaptation. However, more males remained unpaired at a noisy location than at a quiet location throughout the breeding season. Thus, phenotypic plasticity enables individuals to respond to environmental changes, but whether these short-term adjustments are beneficial remains to be seen.

Mathematical modeling of colony formation in algal blooms: phenotypic plasticity in cyanobacteria

In this paper, we analyzed a mathematical model of algal-grazer dynamics, including the effect of colony formation, which is an example of phenotypic plasticity. The model consists of three variables, which correspond to the biomasses of unicellular algae, colonial algae, and herbivorous zooplankton. Among these organisms, colonial algae are the main components of algal blooms. This aquatic system has two stable attractors, which can be identified as a zooplankton-dominated (ZD) state and an algal-dominated (AD) state, respectively. Assuming that the handling time of zooplankton on colonial algae increases with the colonial algae biomass, we discovered that bistability can occur within the model system. The applicability of alternative stable states in algae-grazer dynamics as a framework for explaining the algal blooms in real lake ecosystems, thus, seems to depend on whether the assumption mentioned above is met in natural circumstances.

Cryptic plasticity underlies a major evolutionary transition

The origin of eusociality is often regarded as a change of macroevolutionary proportions [1, 2]. Its hallmark is a reproductive division of labor between the members of a society: some individuals ("helpers" or "workers") forfeit their own reproduction to rear offspring of others ("queens"). In the Hymenoptera (ants, bees, wasps), there have been many transitions in both directions between solitary nesting and sociality [2-5]. How have such transitions occurred? One possibility is that multiple transitions represent repeated evolutionary gains and losses of the traits underpinning sociality. A second possibility, however, is that once sociality has evolved, subsequent transitions represent selection at just one or a small number of loci controlling developmental switches between preexisting alternative phenotypes [2, 6]. We might then expect transitional populations that can express either sociality or solitary nesting, depending on environmental conditions. Here, we use field transplants to directly induce transitions in British and Irish populations of the sweat bee Halictus rubicundus. Individual variation in social phenotype was linked to time available for offspring production, and to the genetic benefits of sociality, suggesting that helping was not simply misplaced parental care [7]. We thereby demonstrate that sociality itself can be truly plastic in a hymenopteran.

First records of oceanic dive profiles for leatherback turtles, Dermochelys coriacea, indicate behavioural plasticity associated with long-distance migration

We used Satellite Relay Data Loggers to obtain the first dive profiles for critically endangered leatherback turtles outside the nesting season. As individuals moved from the Caribbean out into the Atlantic, key aspects of their diving behaviour changed markedly, in line with theoretical predictions for how dive duration should vary with foraging success. In particular, in the Atlantic, where foraging success is expected to be higher, dives became much longer than in the Caribbean. The deepest-ever dive profile recorded for a reptile was obtained in the oceanic Atlantic, with a 54-min dive to 626 m on 26 August 2002. However, dives were typically much shallower (generally