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.