Activation of nicotinic acetylcholine receptors enhances a slow calcium‐dependent potassium conductance and reduces the firing of stratum oriens interneurons

Abstract

A large variety of distinct locally connected GABAergic cells are present in the hippocampus. By releasing GABA into principal cells and interneurons, they exert a powerful control on neuronal excitability and are responsible for network oscillations crucial for information processing in the brain. Here, whole-cell patch clamp recordings in current and voltage clamp mode were used to study the functional role of nicotinic acetylcholine receptors (nAChRs) on the firing properties of stratum oriens interneurons in hippocampal slices from transgenic mice expressing enhanced green fluorescent protein in a subpopulation of GABAergic cells containing somatostatin (GIN mice). Unexpectedly, activation of nAChRs by nicotine or endogenously released acetylcholine strongly enhanced spike frequency adaptation. This effect was blocked by apamin, suggesting the involvement of small calcium-dependent potassium channels (SK channels). Nicotine-induced reduction in firing frequency was dependent on intracellular calcium rise through calcium-permeable nAChRs and voltage-dependent calcium channels activated by the depolarizing action of nicotine. Calcium imaging experiments directly showed that nicotine effects on firing rate were correlated with large increases in intracellular calcium. Furthermore, blocking ryanodine receptors with ryanodine or sarcoplasmic-endoplasmic reticulum calcium ATPase with thapsygargin or cyclopiazonic acid fully prevented the effects of nicotine, suggesting that mobilization of calcium from the internal stores contributed to the observed effects. By regulating cell firing, cholinergic signalling through nAChRs would be instrumental for fine-tuning the output of stratum oriens interneurons and correlated activity at the network level.

Nicotine Blocks the Hyperpolarization-Activated CurrentIhand Severely Impairs the Oscillatory Behavior of Oriens-Lacunosum Moleculare Interneurons

“…In agreement with previous studies (Minneci et al, 2007;Griguoli et al, 2009), O-LM interneurons exhibited a mean resting membrane potential (measured in nonspontaneously active neurons) of 65 Ϯ 0.4 mV and a mean input resistance of 326 Ϯ 16 M⍀ (n ϭ 166). Some of them (122 of 166, 73%) fired spontaneously (the firing frequency ranged between 4 and 9.5 Hz).…”

“…Some of them (122 of 166, 73%) fired spontaneously (the firing frequency ranged between 4 and 9.5 Hz). In addition, these cells exhibited different firing patterns in response to long (400 ms) depolarizing current pulses applied from holding potentials of Ϫ65 and Ϫ75 mV (Minneci et al, 2007;Griguoli et al, 2009), which were maintained with similar characteristics after blocking AMPA/kainate, NMDA, and GABA A receptors with DNQX (20 M), DL-AP-5 (50 M), and gabazine (10 M), respectively. Hyperpolarizing current pulses of different amplitude revealed a sag in the electrotonic potentials, which was mediated by the time-dependent inwardly rectifying cationic current I h (Fig.…”

“…To confer EGFP expression to GABAergic interneurons, an upstream regulatory sequence from the murine Gad1 gene was used for the transgene construction (Oliva et al, 2000). Hippocampal slices were obtained from juvenile (postnatal day 14 -21) using a standard protocol (Griguoli et al, 2009). Briefly, after being anesthetized with an intraperitoneal injection of urethane (2 g/kg), the brain was quickly removed from the skull and placed in ice-cold artificial CSF (ACSF) containing the following (in mM): 130 NaCl, 25 glucose, 3.5 KCl, 1.2 NaH 2 PO 4 , 25 NaHCO 3 , 2 CaCl 2 , and 1.3 MgCl 2 (Sigma), pH 7.3-7.4 (saturated with 95% O 2 and 5% CO 2 ).…”

“…O-LM interneurons receive an important cholinergic innervation from the medial septum-diagonal band complex of the basal forebrain (Frotscher and Léránth, 1985) and are endowed with a variety of muscarinic acetylcholine receptors and nicotinic acetylcholine receptors (nAChRs) (Levey et al, 1995;Tribollet et al, 2004) that regulate their activity (Lawrence et al, 2006;Griguoli et al, 2009). An in vivo study has demonstrated a key role of cholinergic activity in amplifying theta oscillations (Lee et al, 1994), and a recent in vitro work has outlined the role of muscarinic receptors in enhancing spike reliability and precision to theta frequency input (Lawrence et al, 2006).…”

In Hippocampal Oriens Interneurons Anti-Hebbian Long-Term Potentiation Requires Cholinergic Signaling via α7 Nicotinic Acetylcholine Receptors

“…Interestingly, O/A interneurons receive an important cholinergic innervation (Frotscher and Léránth, 1985) and are endowed with nicotinic acetylcholine receptors (nAChRs) which regulate their activity (Frazier et al, 1998;Alkondon et al, 1999;McQuiston and Madison, 1999;Griguoli et al, 2009). Among different nAChR subtypes, ␣7 nAChRs are highly permeable to calcium (Bertrand et al, 1993;Séguéla et al, 1993;Fucile, 2004) and like CP-AMPA receptors exhibit a strong inward rectification which favors calcium entry at relatively negative membrane potentials (Haghighi and Cooper, 1998).…”