Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk.

Cellular signaling involves a large repertoire of membrane receptors operating in overlapping spatiotemporal regimes and targeting many common intracellular effectors. However, both the molecular mechanisms and the physiological roles of crosstalk between receptors, especially those from different superfamilies, are poorly understood. We find that the receptor tyrosine kinase (RTK) TrkB and the G-protein-coupled receptor (GPCR) metabotropic glutamate receptor 5 (mGluR5) together mediate hippocampal synaptic plasticity in response to brain-derived neurotrophic factor (BDNF).

Synaptic plasticity via receptor tyrosine kinase/G protein-coupled receptor crosstalk.

Cellular signaling involves a large repertoire of membrane receptors operating in overlapping spatiotemporal regimes and targeting many common intracellular effectors. However, both the molecular mechanisms and physiological roles of crosstalk between receptors, especially those from different superfamilies, are poorly understood. We find that the receptor tyrosine kinase (RTK), TrkB, and the G protein-coupled receptor (GPCR), metabotropic glutamate receptor 5 (mGluR5), together mediate a novel form of hippocampal synaptic plasticity in response to brain-derived neurotrophic factor (BDNF).

mGreenLantern: a bright monomeric fluorescent protein with rapid expression and cell filling properties for neuronal imaging.

Although ubiquitous in biological studies, the enhanced green and yellow fluorescent proteins (EGFP and EYFP) were not specifically optimized for neuroscience, and their underwhelming brightness and slow expression in brain tissue limits the fidelity of dendritic spine analysis and other indispensable techniques for studying neurodevelopment and plasticity. We hypothesized that EGFP's low solubility in mammalian systems must limit the total fluorescence output of whole cells, and that improving folding efficiency could therefore translate into greater brightness of expressing neurons. By introducing rationally selected combinations of folding-enhancing mutations into GFP templates and screening for brightness and expression rate in human cells, we developed mGreenLantern, a fluorescent protein having up to sixfold greater brightness in cells than EGFP.

Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling.

Caffeine has cognitive-enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor-independent form of LTP ( LTP) in the CA1 region of the hippocampus by promoting calcium-dependent secretion of BDNF, which subsequently activates TrkB-mediated signaling required for the expression of LTP.

Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome.

The cognitive dysfunctions of Down Syndrome (DS) individuals are the most disabling alterations caused by the trisomy of human chromosome 21 (HSA21). In trisomic Ts65Dn mice, a genetic model for DS, the overexpression of HSA21 homologous genes has been associated with strong visuo-spatial cognitive alterations, ascribed to hippocampal dysfunction. In the present study, we evaluated whether the normalization of the expression levels of Dyrk1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A), a candidate gene for DS, might correct hippocampal defects in Ts65Dn mice.

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction.

Background: Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems.

Results: Here we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions.

Flufenamic acid suppresses epileptiform activity in hippocampus by reducing excitatory synaptic transmission and neuronal excitability.

Purpose: In this study, we explore the antiepileptic effects of flufenamic acid (FFA) in order to identify the cellular mechanisms that underlie the potential anticonvulsant properties of this nonsteroidal antiinflammatory compound.

Methods: The mechanisms of FFA action were analyzed using an in vitro model in which epileptiform activity was induced in hippocampal slices by perfusion with 100 microm 4-aminopyridine (4-AP) added to a modified Mg(2+)-free solution. The activity of CA1 pyramidal neurons as well as the synaptic connection between CA3 and CA1 was monitored using extracellular and patch-clamp recordings.