Action of tachykinins in the rat hippocampus: modulation of inhibitory synaptic transmission

Abstract

Substance P and other neuropeptides of the tachykinin family can powerfully excite CA1 hippocampal interneurons present in the CA1 region. In the present work we show that, by exciting hippocampal interneurons, tachykinins can indirectly inhibit pyramidal neurons. We found that tachykinins caused a decrease in the inhibitory synaptic current interval and an increase in the inhibitory synaptic current amplitude in almost all pyramidal neurons tested. This effect was tetrodotoxin sensitive. Tachykinins did not alter the frequency or amplitude of miniature inhibitory synaptic currents and were without effect on evoked inhibitory synaptic currents. Thus, these neuropeptides acted at the somatodendritic membrane of GABAergic interneurons, rather than at their axon terminals. The effect of substance P on spontaneous inhibitory synaptic currents could be mimicked by a selective agonist of NK1 receptors, but not by selective agonists of NK2 and NK3 receptors. It was suppressed by an NK1 receptor antagonist. In CA1 interneurons located in stratum radiatum, substance P generated a sustained tetrodotoxin-insensitive inward current or induced membrane depolarization and action potential firing. This direct excitatory action was mediated by NK1 receptors. Current-voltage relationships indicate that the net tachykinin-evoked current reversed in polarity at or near the K+ equilibrium potential, suggesting that a suppression of a resting K+ conductance was involved. By increasing the excitability of CA1 GABAergic interneurons, tachykinins can powerfully facilitate the inhibitory synaptic input to pyramidal neurons. This indirect inhibition could play a role in regulating short-term and/or long-term synaptic plasticity, promoting neuronal circuit synchronization or, in some physiopathological situations, influencing epileptogenesis.

A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

“…GABAergic synaptic events were recorded in the presence of glutamate receptor antagonists and with high intracellular chloride (see Materials and Methods). Under these conditions, the recorded synaptic events should be exclusively GABAergic, and it was shown previously that they can be blocked by bicuculline (Zaninetti and Raggenbass, 2000;Ogier and Raggenbass, 2003). When applied alone, PNU-120596 produced no detectable change in the frequency of spontaneously occurring synaptic events (baseline ac- 3 M), or the combination of ACh (10 M) and PNU-120596 (0.3 M) was bath applied for an additional 10 min.…”

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…The mechanisms of the proconvulsant effect of substance P are not known yet. Substance P modulates synaptic transmission [166] and can depolarize cortical neurons to elicit an increase in glutamate release at excitatory synapses [167]. Substance P typically affects interneurons, therefore, a facilitation of inhibitory drive to GABA-ergic interneurons may be the mechanism of overexcitation of the epileptic tissue [168].…”

New insights into the regulation of synaptic plasticity from an unexpected place: Hippocampal area CA2

“…Most notably, substance P-expressing SuM efferents target only CA2 in the rat (Borhegyi and Leranth 1997), and bath-applied substance P has been shown to enhance synaptic responses in CA1 (Langosch et al 2005). In addition, substance P increases GABA release by acting on neurokinin-1 receptors, thereby enhancing local inhibitory responses in the hippocampus (Ogier and Raggenbass 2003) and entorhinal cortex (Stacey et al 2002). Interestingly, methods of inducing mild stress, such as exposure to an elevated plus maze (Silveira et al 1993) or immobilization (Choi et al 2012), have been shown to activate neurons in the SuM, presumably resulting in the release of substance P from SuM terminals in CA2.…”