Flavonoid modulation of GABAA receptors

There has been a resurgence of interest in synthetic and plant-derived flavonoids as modulators of γ-amino butyric acid-A (GABAA) receptor function influencing inhibition mediated by the major inhibitory neurotransmitter GABA in the brain. Areas of interest include (i) flavonoids that show subtype selectivity in recombinant receptor studies in vitro consistent with their behavioural effects in vivo, (ii) flumazenil-insensitive modulation of GABAA receptor function by flavonoids, (iii) the ability of some flavonoids to act as second-order modulators of first-order modulation by benzodiazepines and (iv) the identification of the different sites of action of flavonoids on GABAA receptor complexes. An emerging area of interest is the activation of GABAA receptors by flavonoids in the absence of GABA. The relatively rigid shape of flavonoids means that they are useful scaffolds for the design of new therapeutic agents. Like steroids, flavonoids have wide-ranging effects on numerous biological targets. The challenge is to understand the structural determinants of flavonoid effects on particular targets and to develop agents specific for these targets

Modulation and function of the autaptic connections of layer V fast spiking interneurons in the rat neocortex

Neocortical fast-spiking (FS) basket cells form dense autaptic connections that provide inhibitory GABAergic feedback after each action potential. It has been suggested that these autaptic connections are used because synaptic communication is sensitive to neuromodulation, unlike the voltage-sensitive potassium channels in FS cells. Here we show that layer V FS interneurons form autaptic connections that are largely perisomatic, and without perturbing intracellular Cl− homeostasis, that perisomatic GABAergic currents have a reversal potential of −78 ± 4 mV. Using variance–mean analysis, we demonstrate that autaptic connections have a mean of 14 release sites (range 4–26) with a quantal amplitude of 101 ± 16 pA and a probability of release of 0.64 (Vcommand=−70 mV, [Ca2+]o= 2 mm, [Mg2+]o= 1 mm). We found that autaptic GABA release is sensitive to GABAB and muscarinic acetylcholine receptors, but not a range of other classical neuromodulators. Our results indicate that GABA transporters do not regulate FS interneuron autapses, yet autaptically released GABA does not act at GABAB or extrasynaptic GABAA receptors. This research confirms that the autaptic connections of FS cells are indeed susceptible to modulation, though only via specific GABAergic and cholinergic mechanisms