A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein

Prion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein (PrPC) into PrPSc, a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The structure of PrPSc is poorly defined, and likely to be heterogeneous, as suggested by the existence of different prion strains. The latter represents a relevant problem for therapy in prion diseases, as some potent anti-prion compounds have shown strain-specificity. Designing therapeutics that target PrPC may provide an opportunity to overcome these problems. PrPC ligands may theoretically inhibit the replication of multiple prion strains, by acting on the common substrate of any prion replication reaction. Here, we characterized the properties of a cationic tetrapyrrole [Fe(III)-TMPyP], which was previously shown to bind PrPC, and inhibit the replication of a mouse prion strain. We report that the compound is active against multiple prion strains in vitro and in cells. Interestingly, we also find that Fe(III)-TMPyP inhibits several PrPC-related toxic activities, including the channel-forming ability of a PrP mutant, and the PrPC-dependent synaptotoxicity of amyloid-beta (A beta) oligomers, which are associated with Alzheimer's Disease. These results demonstrate that molecules binding to PrPC may produce a dual effect of blocking prion replication and inhibiting PrPC-mediated toxicity

Molecular and cellular mechanisms of dopamine-mediated behavioral plasticity in the striatum

The striatum is the input structure of the basal ganglia system. By integrating glutamatergic signals from cortical and subcortical regions and dopaminergic signals from mesolimbic nuclei the striatum functions as an important neural substrate for procedural and motor learning as well as for reward-guided behaviors. In addition, striatal activity is significantly altered in pathological conditions in which either a loss of dopamine innervation (Parkinson’s disease) or aberrant dopamine-mediated signaling (drug addiction and L-DOPA induced dyskinesia) occurs. Here we discuss cellular mechanisms of striatal synaptic plasticity and aspects of cell signaling underlying striatum-dependent behavior, with a major focus on the neuromodulatory action of the endocannabinoid system and on the role of the Ras–ERK cascade

Viability of Embryo Sacs and Fruit Set in Different Plum (Prunus domestica L.) Cultivars Grown under Norwegian Climatic Conditions

Compatibility and synchrony between specialized tissues of the pistil, female gametophytes and male gametophytes, are necessary for successful pollination, fertilization, and fruit set in angiosperms. The aim of the present work was to study the development and viability of embryo sacs, as well as fertilization success, in relation to the fruit set of the cultivars ‘Mallard’, ‘Edda’, ‘Jubileum’, and ‘Reeves’, under specific Norwegian climatic conditions. Emasculated, unpollinated, and open-pollinated flowers were collected at the beginning of flowering, and on the 3rd, 6th, 9th, and 12th days after flowering, from all four plum cultivars over two years (2018/2019). Ovaries were dehydrated, embedded in paraffin wax, sectioned, stained, and observed under a light microscope. Results showed the existence of synchronization between successive phases in the development of the embryo sac and individual phases of flowering. All plum cultivars had higher percentages of viable embryo sacs, fertilized embryo sacs, and fruit set in 2018 than in 2019. These differences may be related to the very low temperatures during the post-full-flowering period in 2019, and to the low adaptation of some studied cultivars to unfavorable conditions. In our study, the cultivar ‘Jubileum’ showed the highest percentage of viable embryo sacs, fertilized embryo sacs, and fruit set compared to other cultivars, i.e., the best low-temperature adaptation

The effective pollination period of European plum (Prunus domestica L.) cultivars in western Norway

This study evaluated the effective pollination period (EPP) in four European plum (Prunus domestica L.) cultivars (‘Mallard’, ‘Edda’, ‘Jubileum’, and ‘Reeves’) during two years (2018–2019) under the environmental conditions in western Norway. The pollination of plum cultivars was carried out one, three, five, seven, and nine days after anthesis (DAA) with a pollen mix of two compatible cultivars (‘Victoria’ and ‘Opal’). Initial, middle-season, and final fruit set was recorded after one month and two months after pollination and just before the harvest, respectively. On average from both years cultivar ‘Jubileum’ had the highest fruit set when pollinated one, three, five, seven, and nine DAA (33.23%, 30.83%, 8.47%, 3.08%, and 1.15%, respectively), which was more than two folds higher fruit set than in the other studied cultivars. Cultivar ‘Jubileum’ showed significantly reduced fruit set between pollination on five and nine DAA, while cultivars ‘Mallard’, ‘Edda’, and ‘Reeves’ had markedly reduced fruit set if pollinated three to five DAA, implying that the EPP in ‘Jubileum’ was five days while in the rest it was three days. Variation of weather conditions during the flowering period in both years did not have a major effect on the receptivity of stigmas in the studied plum cultivars, which means that the existing differences in the length of EPP is maternal-genotype dependent

Coordinated Regulation of Synaptic Plasticity at Striatopallidal and Striatonigral Neurons Orchestrates Motor Control

The basal ganglia play a critical role in shaping motor behavior. For this function, the activity of medium spiny neurons (MSNs) of the striatonigral and striatopallidal pathways must be integrated. It remains unclear whether the activity of the two pathways is primarily coordinated by synaptic plasticity mechanisms. Using a model of Parkinson’s disease, we determined the circuit and behavioral effects of concurrently regulating cell-type-specific forms of corticostriatal long-term synaptic depression (LTD) by inhibiting small-conductance Ca2+-activated K+ channels (SKs) of the dorsolateral striatum. At striatopallidal synapses, SK channel inhibition rescued the disease-linked deficits in endocannabinoid (eCB)-dependent LTD. At striatonigral cells, inhibition of these channels counteracted a form of adenosine-mediated LTD by activating the ERK cascade. Interfering with eCB-, adenosine-, and ERK signaling in vivo alleviated motor abnormalities, which supports that synaptic modulation of striatal pathways affects behavior. Thus, our results establish a central role of coordinated synaptic plasticity at MSN subpopulations in motor control

Severe intellectual disability and enhanced gamma-aminobutyric acidergic synaptogenesis in a novel model of rare RASopathies

Background Dysregulation of Ras-extracellular signal-related kinase (ERK) signaling gives rise to RASopathies, a class of neurodevelopmental syndromes associated with intellectual disability. Recently, much attention has been directed at models bearing mild forms of RASopathies whose behavioral impairments can be attenuated by inhibiting the Ras-ERK cascade in the adult. Little is known about the brain mechanisms in severe forms of these disorders. Methods We performed an extensive characterization of a new brain-specific model of severe forms of RASopathies, the KRAS12V mutant mouse. Results The KRAS12V mutation results in a severe form of intellectual disability, which parallels mental deficits found in patients bearing mutations in this gene. KRAS12V mice show a severe impairment of both short- and long-term memory in a number of behavioral tasks. At the cellular level, an upregulation of ERK signaling during early phases of postnatal development, but not in the adult state, results in a selective enhancement of synaptogenesis in gamma-aminobutyric acidergic interneurons. The enhancement of ERK activity in interneurons at this critical postnatal time leads to a permanent increase in the inhibitory tone throughout the brain, manifesting in reduced synaptic transmission and long-term plasticity in the hippocampus. In the adult, the behavioral and electrophysiological phenotypes in KRAS12V mice can be temporarily reverted by inhibiting gamma-aminobutyric acid signaling but not by a Ras-ERK blockade. Importantly, the synaptogenesis phenotype can be rescued by a treatment at the developmental stage with Ras-ERK inhibitors. Conclusions These data demonstrate a novel mechanism underlying inhibitory synaptogenesis and provide new insights in understanding mental dysfunctions associated to RASopathies

Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2

Alpha-synuclein oligomers (α-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and α-syn still remains elusive, increasing evidence suggests that extracellular moieties activate glial cells leading to neuronal damage. Using an acute mouse model, we explored whether α-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement.We found that α-synOs abolished mouse memory establishment in association to hippocampal glial activation. On brain slices α-synOs inhibited long-term potentiation. Indomethacin and Ibuprofen prevented the α-synOs-mediated detrimental actions. Furthermore, while the TLR2 functional inhibitor antibody prevented the memory deficit, oligomers induced memory deficits in the TLR4 knockout mice.In conclusion, solely α-synOs induce memory impairment likely inhibiting synaptic plasticity. α-synOs lead to hippocampal gliosis that is involved in memory impairment. Moreover, while the oligomer-mediated detrimental actions are TLR2 dependent, the involvement of TLR4 was ruled out

Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy

We recently discovered that forebrain activation of the IL-1 receptor/Toll-like receptor (IL-1R1/TLR4) innate immunity signal plays a pivotal role in neuronal hyperexcitability underlying seizures in rodents. Since this pathway is activated in neurons and glia in human epileptogenic foci, it represents a potential target for developing drugs interfering with the mechanisms of epileptogenesis that lead to spontaneous seizures. The lack of such drugs represents a major unmet clinical need. We tested therefore novel therapies inhibiting the IL-1R1/TLR4 signaling in an established murine model of acquired epilepsy. We used an epigenetic approach by injecting a synthetic mimic of micro(mi)RNA-146a that impairs IL1R1/TLR4 signal transduction, or we blocked receptor activation with antiinflammatory drugs. Both interventions when transiently applied to mice after epilepsy onset, prevented disease progression and dramatically reduced chronic seizure recurrence, while the anticonvulsant drug carbamazepine was ineffective. We conclude that IL-1R1/TLR4 is a novel potential therapeutic target for attaining disease-modifications in patients with diagnosed epilepsy. (C) 2016 Elsevier Inc. All rights reserve