In biological complexes, cascade structures promote the spatial separation of photogenerated electrons and holes, preventing their recombination. In contrast, the photogenerated excitons in organic ...photovoltaic cells are dissociated at a single donor-acceptor heterojunction formed within a de-mixed blend of the donor and acceptor semiconductors. The nanoscale morphology and high charge densities give a high rate of electron-hole encounters, which should in principle result in the formation of spin-triplet excitons, as in organic light-emitting diodes. Although organic photovoltaic cells would have poor quantum efficiencies if every encounter led to recombination, state-of-the-art examples nevertheless demonstrate near-unity quantum efficiency. Here we show that this suppression of recombination arises through the interplay between spin, energetics and delocalization of electronic excitations in organic semiconductors. We use time-resolved spectroscopy to study a series of model high-efficiency polymer-fullerene systems in which the lowest-energy molecular triplet exciton (T1) for the polymer is lower in energy than the intermolecular charge transfer state. We observe the formation of T1 states following bimolecular recombination, indicating that encounters of spin-uncorrelated electrons and holes generate charge transfer states with both spin-singlet ((1)CT) and spin-triplet ((3)CT) characters. We show that the formation of triplet excitons can be the main loss mechanism in organic photovoltaic cells. But we also find that, even when energetically favoured, the relaxation of (3)CT states to T1 states can be strongly suppressed by wavefunction delocalization, allowing for the dissociation of (3)CT states back to free charges, thereby reducing recombination and enhancing device performance. Our results point towards new design rules both for photoconversion systems, enabling the suppression of electron-hole recombination, and for organic light-emitting diodes, avoiding the formation of triplet excitons and enhancing fluorescence efficiency.
Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor function ...are altered, thus making AMPA receptors potential therapeutic targets for clinical intervention. The work summarized in this review suggests a link between AMPA receptor function and debilitating neuropathologies, and discusses the current state of therapies targeting AMPA receptors in four diseases. In amyotrophic lateral sclerosis, AMPA receptors allow cytotoxic levels of calcium into neurons, leading to motor neuron death. Likewise, in some epilepsies, overactivation of AMPA receptors leads to neuron damage. The same is true for ischemia, where oxygen deprivation leads to excitotoxicity. Conversely, Alzheimer’s disease is characterized by decreased AMPA activation and synapse loss. Unfortunately, many clinical studies have had limited success by directly targeting AMPA receptors in these diseases. We also discuss how the use of AMPA receptor modulators, commonly known as ampakines, in neurological diseases initially seemed promising in animal studies, but mostly ineffective in clinical trials. We propose that indirectly affecting AMPA receptors, such as by modulating transmembrane AMPA receptor regulatory proteins or, more generally, by regulating glutamatergic transmission, may provide new therapeutic potential for neurological disorders.
Many neurological diseases are manifested by changes in synaptic transmission and plasticity. As AMPA receptors are the workhorses in excitatory neurotransmission, we review the potential, as well as pitfalls, for targeting these receptors in four different neuropathologies.
Hyperactivity of microglia and loss of functional circuitry is a common feature of many neurological disorders including those induced or exacerbated by inflammation. Herein, we investigate the ...response of microglia and changes in hippocampal dendritic postsynaptic spines by dendritic polyglycerol sulfate (dPGS) treatment. Mouse microglia and organotypic hippocampal slices were exposed to dPGS and an inflammogen (lipopolysaccharides). Measurements of intracellular fluorescence and confocal microscopic analyses revealed that dPGS is avidly internalized by microglia but not CA1 pyramidal neurons. Concentration and time-dependent response studies consistently showed no obvious toxicity of dPGS. The adverse effects induced by proinflammogen LPS exposure were reduced and dendritic spine morphology was normalized with the addition of dPGS. This was accompanied by a significant reduction in nitrite and proinflammatory cytokines (TNF-α and IL-6) from hyperactive microglia suggesting normalized circuitry function with dPGS treatment. Collectively, these results suggest that dPGS acts anti-inflammatory, inhibits inflammation-induced degenerative changes in microglia phenotype and rescues dendritic spine morphology.
Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has ...been shown that ablating tropomyosin‐related kinase B (TrkB), a receptor for brain‐derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF‐mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury‐induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB‐Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB‐Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two‐fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB‐Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB‐Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury‐induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post‐traumatic epilepsy. Therefore, our data suggest that blocking the BDNF–TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post‐traumatic epilepsy.
Here, we report that following Schaffer collateral lesion, Brain‐Derived Neurotrophic Factor (BDNF) release can lead to axonal sprouting and hyperexcitability of area CA3 pyramidal neurons. Moreover, using patch‐clamp and field EPSP recordings we show that this hyperexcitability is not due to changes in intrinsic electrical properties of CA3 pyramidal neurons, but rather through BDNF‐dependent synapse formation.
CX 546, an allosteric positive modulator of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid‐type ionotropic glutamate receptors (AMPARs), belongs to a drug class called ampakines. These ...compounds have been shown to enhance long‐term potentiation (LTP), a cellular model of learning and memory, and improve animal learning task performance, and have augmented cognition in neurodegenerative patients. However, the chronic effect of CX546 on synaptic structures has not been examined. The structure and integrity of dendritic spines are thought to play a role in learning and memory, and their abnormalities have been implicated in cognitive disorders. In addition, their structural plasticity has been shown to be important for cognitive function, such that dendritic spine remodeling has been proposed as the morphological correlate for LTP. Here, we tested the effect of CX546 on dendritic spine remodeling following long‐term treatment. We found that, with prolonged CX546 treatment, organotypic hippocampal slice cultures showed a significant reduction in CA3–CA1 excitatory synapse and spine density. Electrophysiological approaches revealed that the CA3–CA1 circuitry compensates for this synapse loss by increasing synaptic efficacy through enhancement of presynaptic release probability. CX546‐treated slices showed prolonged and enhanced potentiation upon LTP induction. Furthermore, structural plasticity, namely spine head enlargement, was also more pronounced after CX546 treatment. Our results suggest a concordance of functional and structural changes that is enhanced with prolonged CX546 exposure. Thus, the improved cognitive ability of patients receiving ampakine treatment may result from the priming of synapses through increases in the structural plasticity and functional reliability of hippocampal synapses.
Here, we report that chronic treatment with the ampakine, CX546, results in the loss of excitatory synapses and dendritic spines in CA1 pyramidal neurons of the hippocampus. At the same time, chronic CX546 treatment enhances presynaptic release probability and both structural and functional plasticity following LTP induction. Our findings suggest that neurons are conditioned by ampakine to be more responsive to learning paradigms; thus improving cognitive functions.
Microglia interact with neurons to facilitate synapse plasticity; however, signal(s) contributing to microglia activation for synapse elimination in pathology are not fully understood. Here, using in ...vitro organotypic hippocampal slice cultures and transient middle cerebral artery occlusion (MCAO) in genetically engineered mice in vivo, we report that at 24 hours after ischemia, microglia release brain-derived neurotrophic factor (BDNF) to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the cornu ammonis 1 (CA1) in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75 neurotrophin receptor (p75
) and tropomyosin receptor kinase B (TrkB) receptors, respectively. After MCAO, we report that in the peri-infarct area and in the corresponding contralateral hemisphere, similar neuroplasticity occurs through microglia activation and gephyrin phosphorylation at serine-268 and serine-270 in vivo. Targeted deletion of the
gene in microglia or
S268A/S270A (phospho-null) point mutations protects against ischemic brain damage, neuroinflammation, and synapse downregulation after MCAO.
Epilepsy is a chronic brain disorder involving recurring seizures often precipitated by an earlier neuronal insult. The mechanisms that link the transient neuronal insult to the lasting state of ...epilepsy are unknown. Here we tested the possible role of DNA methylation in mediating long-term induction of epileptiform activity by transient kainic acid exposure using in vitro and in vivo rodent models. We analyzed changes in the gria2 gene, which encodes for the GluA2 subunit of the ionotropic glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor and is well documented to play a role in epilepsy. We show that kainic acid exposure for two hours to mouse hippocampal slices triggers methylation of a 5' regulatory region of the gria2 gene. Increase in methylation persists one week after removal of the drug, with concurrent suppression of gria2 mRNA expression levels. The degree of kainic acid-induced hypermethylation of gria2 5' region varies between individual slices and correlates with the changes in excitability induced by kainic acid. In a rat in vivo model of post kainic acid-induced epilepsy, we show similar hypermethylation of the 5' region of gria2. Inter-individual variations in gria2 methylation, correlate with the frequency and intensity of seizures among epileptic rats. Luciferase reporter assays support a regulatory role for methylation of gria2 5' region. Inhibition of DNA methylation by RG108 blocked kainic acid-induced hypermethylation of gria2 5' region in hippocampal slice cultures and bursting activity. Our results suggest that DNA methylation of such genes as gria2 mediates persistent epileptiform activity and inter-individual differences in the epileptic response to neuronal insult and that pharmacological agents that block DNA methylation inhibit epileptiform activity raising the prospect of DNA methylation inhibitors in epilepsy therapeutics.
Christianson Syndrome is a rare but increasingly diagnosed X-linked intellectual disability disorder that arises from mutations in SLC9A6/NHE6, a pH-regulating transporter that localizes to early and ...recycling endosomes. We have recently reported that one of the originally identified disease-causing mutations in NHE6 (p.E287-S288del, or ΔES) resulted in a loss of its pH regulatory function. However, the impact of this mutation upon neuronal synapse formation and plasticity is unknown. Here, we investigate the consequences of the ΔES mutant upon mouse hippocampal pyramidal neurons by expressing a fluorescently-labeled ΔES NHE6 construct into primary hippocampal neurons. Neurons expressing the ΔES mutant showed significant reductions in mature dendritic spine density with a concurrent increase in immature filopodia. Furthermore, compared to wild-type (WT), ΔES-containing endosomes are redirected away from early and recycling endosomes toward lysosomes. In parallel, the ΔES mutant reduced the trafficking of glutamatergic AMPA receptors to excitatory synapses and increased their accumulation within lysosomes for potential degradation. Upon long-term potentiation (LTP), neurons expressing ΔES failed to undergo significant structural and functional changes as observed in controls and WT transfectants. Interestingly, synapse density and LTP-induced synaptic remodeling in ΔES-expressing neurons were partially restored by bafilomycin, a vesicular alkalinisation agent, or by leupeptin, an inhibitor of lysosomal proteolytic degradation. Overall, our results demonstrate that the ∆ES mutation attenuates synapse density and structural and functional plasticity in hippocampal neurons. These deficits may be partially due to the mistargeting of AMPA receptors and other cargos to lysosomes, thereby preventing their trafficking during synaptic remodeling. This mechanism may contribute to the cognitive learning deficits observed in patients with Christianson Syndrome and suggests a potential therapeutic strategy for treatment.
•A deletion mutation in NHE6 (ΔES) reduces dendritic spines in hippocampal neurons.•NHE6 ΔES is mislocalized and increases AMPA receptor trafficking to lysosomes.•The ΔES mutant impairs structural and functional remodeling after induction of LTP.•Lysosomal inhibition partially restores spine density and plasticity in ΔES-expressing cells.
The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 ...oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets a relatively well-defined population of low-n Aβ42 oligomers, rather than simply inhibiting the aggregation of Aβ monomers into oligomers. Our data show that AIP diminishes the loss of Aβ42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Aβ42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically "trapping" low-n oligomers provides a novel strategy for toxic Aβ42-oligomer recognition and removal.
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