Abstracts

Rationale: GABAergic interneurons play a key role in the control of neuronal excitability, and they are known to undergo lasting changes at the single cell, synapse, and circuit levels after seizures. GABA-release from cholecystokinin-positive (CCK+) perisomatically projecting basket cells (BCs) is known to be powerfully regulated by presynaptic cannabinoid type 1 receptors (CB1Rs), and the CB1R-mediated control of GABA-release has been shown to undergo significant, long-lasting alterations after seizures. The control of GABA-release from CCK+ BCs by CB1Rs occurs in both tonic and phasic forms, including the control of tonic GABA release, the depolarization-induced suppression of inhibition (DSI), and the suppression of GABA-release that can take place following agonist-induced activation of Gq/11-GPCRs. However, in addition to CCK+ BCs, dendritically projecting CCK+ interneurons, the so-called Schaffer collateral associated interneurons (SCAs), are also known to provide extensive GABAergic innervation to pyramidal cells, but the regulation of GABA-release from SCAs by CB1Rs is not understood. In the current study, we examined whether the control of GABA release by CB1R from BCs is different from that from SCAs. Methods: Paired recordings were performed from presynaptic CCK+ BCs or SCAs and postsynaptic pyramidal cells in the rat CA1. The two types of CCK+ interneurons were identified based on their firing properties, immunocytochemistry, and axonal projection patterns. All presynaptic cells were tested for CCK and PV immunoreactivity and the coexpression of two markers was never observed. The axonal and dendritic arbors of all presynaptic cells were also determined. Results: Paired recordings revealed that unitary IPSCs at the SCA-to-pyramidal cell synapses were smaller and slower than those at the BC-to-pyramidal cell synapses, whereas the proportion of presynaptic action potentials that caused IPSCs did not differ. Asynchronous GABA release was significantly more powerful from SCAs. While CB1R agonists abolished GABA release from both cell types indicating the presence of functional CB1R on both interneuronal types, SCAs exhibited significantly weaker type 1 mGluR-mediated suppression, DSI, and tonic inhibition of GABA release compared to CCK+ BCs. Conclusions: CB1Rs provide highly selective, differential control of GABA-release from perisomatically and dendritically projecting CCK+ interneurons in the CA1 hippocampus. Since seizures are known to significantly alter the expression of CB1Rs in a long-term manner in several experimental epilepsy paradigms including pilocarpine-induced status epilepticus and experimental febrile seizures, future research will need to determine how the marked differences in CB1R-mediated regulation of GABA-release is altered in an activity-dependent manner by seizures at perisomatic versus dendritic synapses. This works was supported by the NIH (NS38580 to I.S.) and by the Epilepsy Foundation through the generous support of the Eric W. Lothman Training Fellowship (to S.L.).