Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity in the hippocampus, but the mechanisms involved are not fully understood. The neurotrophin couples synaptic activation to changes in gene expression underlying long term potentiation and short term plasticity. Here we show that BDNF acutely up-regulates GluR1, GluR2, and GluR3 ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits in 7-day tropomyosin-related kinase in vitro cultured hippocampal neurons. The increase in GluR1 and GluR2 protein levels in developing cultures was impaired by K252a, a Trk inhibitor, and by translation (emetine and anisomycin) and transcription (␣-amanitine and actinomycin D) inhibitors. Accordingly, BDNF increased the mRNA levels for GluR1 and GluR2 subunits. Biotinylation studies showed that stimulation with BDNF for 30 min selectively increased the amount of GluR1 associated with the plasma membrane, and this effect was abrogated by emetine. Under the same conditions, BDNF induced GluR1 phosphorylation on Ser-831 through activation of protein kinase C and Ca 2؉ -calmodulin-dependent protein kinase II. Chelation of endogenous extracellular BDNF with TrkB-IgG selectively decreased GluR1 protein levels in 14-day in vitro cultures of hippocampal neurons. Moreover, BDNF promoted synaptic delivery of homomeric GluR1 AMPA receptors in cultured organotypic slices, by a mechanism independent of NMDA receptor activation. Taken together, the results indicate that BDNF up-regulates the protein levels of AMPA receptor subunits in hippocampal neurons and induces the delivery of AMPA receptors to the synapse.Neurotrophins are essential for the development of the vertebrate nervous system, modulate synaptic function, and play an important role in synaptic plasticity (1, 2). Brain-derived neurotrophic factor (BDNF) 3 has been implicated in activitydependent synaptic plasticity, particularly in long term potentiation (LTP) induced by high frequency stimulation. Accordingly, LTP is impaired in the hippocampal CA1 region of animals deficient in BDNF, but it can be rescued by supplying the neurotrophin (3-5). Chelation of endogenous BDNF also prevents the induction of LTP by theta burst stimulation and reduces late phase LTP induced by high frequency stimulation (6, 7). Furthermore, the late phase LTP induced by tetanic stimulation was not observed in slices from BDNF knock-out mice and was also abrogated when TrkB receptors were blocked (8). Taken together, the available evidences point to a direct role of BDNF in the early and late phases of LTP.Binding of BDNF to TrkB receptors is followed by activation of intracellular signaling pathways, including the Ras/extracellular signal-regulated protein kinase, phospholipase C␥ (PLC␥), phosphatidylinositol-3-kinase/Akt, and Src pathways (9 -11). TrkB receptors are located on axon terminals and in the post-synaptic density of glutamatergic synapses (12-14), but whether the effects of BDNF on synaptic plasticity are mediated by pre-and/or post-sy...

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Photoacoustic calorimetry was used to measure the quantum yields of singlet molecular oxygen production by the triplet states of tetraphenylporphyrin (TPP), ZnÀTPP and CuÀTPP in toluene, yielding values of 0.67 AE 0.14, 0.68 AE 0.19 and 0.03 AE 0.01, respectively. We show that a novel dichlorophenyl derivative of Zn À TPP is capable of singlet-oxygen production with a 0.90 AE 0.07 quantum yield. The synthesis and characterisation of a new photostable chlorin with high absorptivity in the red that is capable of singlet-oxygen production with 0.54 AE 0.06 quantum yield is described. Our results suggest that chlorinated chlorins may be interesting new sensitisers for photodynamic therapy.

The neurotrophin brain-derived neurotrophic factor (BDNF) plays an important role in the activity-dependent regulation of synaptic structure and function, particularly of the glutamatergic synapses. BDNF may be released in the mature form, which activates preferentially TrkB receptors, or as proBDNF, which is coupled to the stimulation of the p75 NTR . In the mature form BDNF induces rapid effects on glutamate release, and may induce short-and long-term effects on the postsynaptic response to the neurotransmitter. BDNF may affect glutamate receptor activity by inducing the phosphorylation of the receptor subunits, which may also affect the interaction with intracellular proteins and, consequently, their recycling and localization to defined postsynaptic sites. Stimulation of the local protein synthesis and transcription activity account for the delayed effects of BDNF on glutamatergic synaptic strength. Several evidences show impaired synaptic plasticity of glutamatergic synapses in diseases where compromised BDNF function has been observed, such as Huntington's disease, depression, anxiety, and the BDNF polymorphism Val66Met, suggesting that upregulating BDNF-activated pathways may be therapeutically relevant. This review focuses on recent advances in the understanding of the regulation of the glutamatergic synapse by BDNF, and its implications in synaptic plasticity.

The neurotrophin BDNF regulates the activity-dependent modifications of synaptic strength in the CNS. Physiological and biochemical evidences implicate the NMDA glutamate receptor as one of the targets for BDNF modulation. In the present study, we investigated the effect of BDNF on the expression and plasma membrane abundance of NMDA receptor subunits in cultured hippocampal neurons. Acute stimulation of hippocampal neurons with BDNF differentially upregulated the protein levels of the NR1, NR2A and NR2B NMDA receptor subunits, by a mechanism sensitive to transcription and translation inhibitors. Accordingly, BDNF also increased the mRNA levels for NR1, NR2A and NR2B subunits. The neurotrophin NT3 also upregulated the protein levels of NR2A and NR2B subunits, but was without effect on the NR1 subunit. The amount of NR1, NR2A and NR2B proteins associated with the plasma membrane of hippocampal neurons was differentially increased by BDNF stimulation for 30 min or 24 h. The rapid upregulation of plasma membrane-associated NMDA receptor subunits was correlated with an increase in NMDA receptor activity. The results indicate that BDNF increases the abundance of NMDA receptors and their delivery to the plasma membrane, thereby upregulating receptor activity in cultured hippocampal neurons.

Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV), to generate an in vivo MJD genetic model and, to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD. LV encoding mutant or wild-type human ataxin-3 was injected in the brain of adult rats and the animals were tested for behavioral deficits and neuropathological abnormalities. Striatal pathology was confirmed in transgenic mice and human tissue. In substantia nigra, unilateral overexpression of mutant ataxin-3 led to: apomorphine-induced turning behavior; formation of ubiquitinated ataxin-3 aggregates; alpha-synuclein immunoreactivity; and loss of dopaminergic markers (TH and VMAT2). No neuropathological changes were observed upon wild-type ataxin-3 overexpression. Mutant ataxin-3 expression in striatum and cortex, resulted in accumulation of misfolded ataxin-3, and within striatum, loss of neuronal markers. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and alpha-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapies.

Brain development, sensory information processing, and learning and memory processes depend on Hebbian forms of synaptic plasticity, and on the remodeling and pruning of synaptic connections. Neurons in networks implicated in these processes carry out their functions while facing constant perturbation; homeostatic responses are therefore required to maintain neuronal activity within functional ranges for proper brain function. Here, we will review in vitro and in vivo studies demonstrating that several mechanisms underlie homeostatic plasticity of excitatory synapses, and identifying participant molecular players. Emerging evidence suggests a link between disrupted homeostatic synaptic plasticity and neuropsychiatric and neurologic disorders. Keywords: AMPA receptors, experience-dependent plasticity, Hebbian synaptic plasticity, homeostatic synaptic plasticity, synapse, synaptic scaling.This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Hebbian and homeostatic synaptic plasticityLearning and memory as well as other forms of human behavior possibly rely on the ability of the mammalian brain to undergo experience-based adaptations in synaptic strength, which becomes stronger or weaker in response to specific patterns of activity. Hebbian synaptic plasticity is the most widely studied form of long-lasting activity-dependent changes in synaptic strength and includes both long-term potentiation (LTP) and its counterpart, long-term depression (LTD). Hebbian forms of plasticity typically function in an input-specific manner, are rapidly induced and long-lasting, and require correlated firing of the pre-and post-synaptic neurons (Malenka and Bear 2004;Luscher and Malenka 2012;Huganir and Nicoll 2013). Because these hallmark features facilitate the reinforcement of precise synaptic connections, which is fundamental for information storage in the brain, these Hebbian mechanisms are thought to be the cellular correlates of learning and memory. However, these same features of Hebbian plasticity pose a stability problem to neural networks. The requirement of correlated activity to reinforce useful pathways in the brain provokes positive feedback loops of activity-dependent changes in synaptic strength. For instance, once LTP is induced, potentiated synapses are more excitable and can undergo further potentiation more easily, entering a cycle that, if unconstrained, eventually drives activity to a state prone to hyperexcitability

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