Abstracts

Perisomatic inhibitory input from GABAergic basket cells has a major influence on action potential generation and spike timing of CA1 pyramidal cells. A particular feature of cholecystokinin- (CCK) positive basket cell input is that it can be selectively silenced by presynaptic cannabinoid receptors, both by the activity-dependent synthesis and release of endocannabinoids from the postsynaptic cells (a process known as depolarization-induced suppression of inhibition or DSI), and by the constitutive activity of the CB1 receptors (Losonczy et al., PNAS 2004). Importantly, developmental seizures persistently increase the number and constitutive activity of CB1 receptors (Chen et al., Neuron 2003). Here we tested the hypothesis that the cannabinoid-mediated inhibition of GABA-release not only depends on postsynaptic factors, but also on the level of activity in the presynaptic interneurons. Paired patch clamp recordings were used to investigate the mechanism of cannabinoid actions at synapses between CA1 pyramidal cells and immunocytochemically identified CCK+ basket cells. Action potentials in the presynaptic basket cells evoked large IPSCs with fast kinetics in CA1 pyramidal cells, that were completely abolished by the application of the CB1 receptor agonist WIN 55,212-2. However, when the firing frequency of the presynaptic cell was increased to 40 Hz, synaptic transmission re-appeared, in spite of the continued presence of the agonist. This overrun of the cannabinoid-effect could be blocked by application of the N-type calcium-channel blocker conotoxin. In addition, subsequent experiments showed that the presynaptic activity-dependent release mechanism was also effective during DSI. These data show that the selective modulation of a specific subset of perisomatic GABAergic input by cannabinoid receptors is dependent on both the pre- and the postsynaptic cells[apos] output. The frequency-dependence of DSI at identified synapses provides new insights into the modulation of inhibitory neurotransmission. (Supported by NINDS (NS38580 to IS), German Research Council (NE 1185/1-1 to AN).)