title: Modulatory effects of the novel TrkB receptor agonist 7,8-dihydroxyflavone on synaptic transmission and intrinsic neuronal excitability in mouse visual cortex in vitro.
abstract: 7,8-Dihydroxyflavone (7,8 DHF) is a new recently identified TrkB receptor agonist, which possesses a potent neurotrophic activity and shares many physiological properties with the neurotrophin "Brain Derived Neurotrophic Factor" (BDNF). However, its precise mechanism of action at the cellular level has not been clarified yet. In the present study we explored the effects of this agent on synaptic and intrinsic neuronal properties by performing whole-cell patch clamp recordings from layer 2/3 pyramidal neurons. Incubation of acute cortical slices with 7,8-DHF (20 µM) for 30 min caused a selective reduction in the strength of GABAergic inhibition. The amplitude of evoked inhibitory postsynaptic currents (eIPSCs) was significantly reduced to 48.2±8.9% of the control level. This might be a result of decreased presynaptic γ-aminobutyric acid (GABA) release, as suggested by the reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs) (control: 10.7±0.7 Hz, 7,8 DHF: 7.9±0.6 Hz) and increased Paired-Pulse Ratio (PPR) (50±8.9%). Conversely, the glutamatergic transmission was unaffected. Moreover, 7,8-DHF was able to alter the intrinsic neuronal excitability, by significantly increasing spike frequency and input resistance (control: 243.75±23.4 MΩ, 7,8 DHF: 338.5±25.1 MΩ). Remarkably, all reported effects were abolished in presence of the TrkB receptor antagonist K252a indicating a direct involvement of TrkB receptors in the action of 7,8-DHF. These data indicate that 7,8-DHF might be one promising candidate for the development of a new class of drugs called "BDNF mimetics" for the future treatment of cognitive disorders and neurodegenerative diseases.
authors.affiliation: Institute of Physiology and Pathophysiology, University Medical Center of the Johannes-Gutenberg University Mainz, Duesbergweg 6, D-55128 Mainz, Germany.
authors.forename: Daniele
authors.initials: D
authors.lastname: Marongiu
authors.forename: Barbara
authors.initials: B
authors.lastname: Imbrosci
authors.forename: Thomas
authors.initials: T
authors.lastname: Mittmann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017097:Electric Impedance; D005074:Evoked Potentials, Visual / Q000187:drug effects; D047309:Flavones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018697:Nootropic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020813:Receptor, trkB / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D014793:Visual Cortex / Q000187:drug effects* / Q000378:metabolism
chemical_list: C485383:6,7-dihydroxyflavone; D047309:Flavones; D058787:GABA-A Receptor Antagonists; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D047428:Protein Kinase Inhibitors; D011963:Receptors, GABA-A; D020813:Receptor, trkB