Inhibition and Disinhibition of Pyramidal Neurons by Activation of Nicotinic Receptors on Hippocampal Interneurons

Abstract

Nicotinic acetylcholine receptors (nAChRs) are expressed in the hippocampus, and their functional roles are beginning to be delineated. The effect of nAChR activation on the activity of both interneurons and pyramidal neurons in the CA1 region was studied in rat hippocampal slices. In CA1 stratum radiatum with muscarinic receptors inhibited, local pressure application of acetylcholine (ACh) elicited a nicotinic current in 82% of the neurons. The majority of the ACh-induced currents were sensitive to methyllycaconitine, which is a specific inhibitor of alpha7-containing nAChRs. Methyllycaconitine-insensitive nicotinic currents also were present as detected by a nonspecific nAChR inhibitor. The ACh-sensitive neurons in the s. radiatum were identified as GABAergic interneurons by their electrophysiological properties. Pressure application of ACh induced firing of action potentials in approximately 70% of the interneurons. The ACh-induced excitation of interneurons could induce either inhibition or disinhibition of pyramidal neurons. The inhibition was recorded from the pyramidal neuron as a burst of GABAergic synaptic activity. That synaptic activity was sensitive to bicuculline, indicating that GABA(A) receptors mediated the ACh-induced synaptic currents. The disinhibition was recorded from the pyramidal neuron as a reduction of spontaneous GABAergic synaptic activity when ACh was delivered onto an interneuron. Both the inhibition and disinhibition were sensitive to either methyllycaconitine or mecamylamine, indicating that activation of nicotinic receptors on interneurons was necessary for the effects. These results show that nAChRs are capable of regulating hippocampal circuits by exciting interneurons and, subsequently, inhibiting or disinhibiting pyramidal neurons.

Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

“…For example, two hippocampal pyramidal cells connected to the same GABAergic interneuron readily synchronize their firing after recovering from the inhibition evoked by the interneuron (25). Also, in the hippocampus, ACh-dependent activation of interneurons produces inhibition of pyramidal cells followed by rebound spiking (26), and endogenous cortical ACh recently has been shown to enhance synchronized interneuron activity via activation of ␣4␤2 nAChRs (27). Importantly, in human focal cortical dysplasia tissue in vitro ictal activity is initiated via a synchronization mechanism that requires sustained activation of GABA A receptors (28).…”

Altered hippocampal circuit function in C3H α7 null mutant heterozygous mice

“…These findings suggest that activation of α7 receptors could influence GABA release in the hippocampus. Physiological studies in rat hippocampal slices have confirmed the presence of α7 receptors on interneurons in all layers of area CA1 (Alkondon et al, 1998;Buhler and Dunwiddie, 2001;Frazier et al, 1998b;Frazier et al, 1998a;Jones and Yakel, 1997;McQuiston and Madison, 1999) as well as GABA-mediated inhibition of CA1 pyramidal cells following activation of α7 receptors on CA1 interneurons (Alkondon and Albuquerque, 2001;Buhler and Dunwiddie, 2002;Ji and Dani, 2000). It seems reasonable to hypothesize that α7 receptors may also modulate GABA release from interneurons in hippocampal area CA3 given that α-BTX binding has been observed on CA3 interneuron subtypes (Freedman et al, 1993) that are known to make synaptic contact with CA3 pyramidal cells (Freund and Buzsaki, 1996).…”

Cellular and synaptic mechanisms of nicotine addiction

“…In addition, nAChRs can modulate GABAergic transmission in multiple brain areas, such as thalamus, cortex, hippocampus, and interpeduncular nucleus (Lena et al, 1993;Alkondon et al, 1997Alkondon et al, , 2000Lena and Changeux, 1997;Fisher et al, 1998;Radcliffe et al, 1999). Modulation of GABA neurons by nAChRs has been most extensively studied in the hippocampus, where GABAergic interneurons express multiple nAChR subtypes (Alkondon et al, 1997;Jones and Yakel, 1997;Frazier et al, 1998b;McQuiston and Madison, 1999;Ji and Dani, 2000). The physiologic impact of nAChR activation is critically dependent upon their localization.…”