Cholinergic receptor–independent modulation of intrinsic resonance in the rat subiculum neurons through inhibition of hyperpolarization‐activated cyclic nucleotide‐gated channels

Abstract

Aim Acetylcholine release is vital in the pacing of theta rhythms in the hippocampus. The subiculum is the output region of the hippocampus with different neuronal subtypes that generate theta oscillations during arousal and rapid eye movement sleep. The combination of intrinsic resonance in the hippocampal neurons and the periodic excitation of hippocampal excitatory and inhibitory neurons by cholinergic pathway drives theta oscillations. However, the acetylcholine mediated effect on intrinsic subthreshold resonance generating hyperpolarization‐activated cyclic nucleotide‐gated current, Ih of subicular neurons is unexplored. We studied the acetylcholine receptor‐independent effect of cholinergic agents on the intrinsic properties of subiculum principal neurons and the underlying mechanism. Methods We bath perfused acetylcholine or nicotine on rat brain slices in the presence of synaptic blockers. The physiological effect was studied by cholinergic fibres stimulation and electrophysiological recordings under whole‐cell mode of subiculum neurons using septohippocampal sections. Results Exogenously applied acetylcholine in the presence of atropine affected two groups of subicular neurons differently. Acetylcholine reduced the resonance frequency and Ih in bursting neurons, whereas these properties were unaffected in regular firing neurons. Subsequently, the endogenously released acetylcholine by stimulation showed a selective suppressive effect on Ih, sag, and resonance in burst firing among the two excitatory neurons. Nicotine suppressed the Ih amplitude in burst firing neurons, which was evident by decreased sag amplitude and resonance frequency and increased excitability. Conclusion Our study suggests cell type‐specific acetylcholine receptor‐independent shift in resonance frequency by partially inhibiting HCN current during high cholinergic inputs.

HCN and nicotine

“…1 As confirmed also in the subiculum, nicotine may directly modulate the hyperpolarization-activated cyclic nucleotidegated (HCN) non-selective cation channel. 2 The latter mirrors findings in interneurons of stratum oriens (SO) with axons terminating within the lacunosum moleculare (SLM) of the hippocampus. 3 It is consistent that the main role of HCN and underlying currents I h to some extent is dogmatized, as its functional expression in the hippocampus and subiculum does not make them pacemaker regions.…”

“…Despite changing the frequency every second by 1 Hz, the 20 Hz range was not achieved in figure 3Db,C. 2 In figure 1Db,C the estimated frequencies were 4.1 ± 0.2 vs 2.1 ± 0.1 Hz for IB and RS neurons, while in figure 3Dd, 3.7 ± 0.3 vs 2.5 ± 0.1 Hz. Corresponding peaks are hard to distinguish in figure 3Db,C because of overlap.…”

“…9 When the bursting is intrinsic, then it occurs around the rheobase that could vary among neurons, but not too apart from +50 pA (Figure 1A). It is not clear why all four neurons in figure 7Dd require a rheobase of +200 pA. 2 Phenotypes of IB and regular spiking (RS) neurons in figure 5 Da,B are not apart. Also comparable changes after input priming reveal that two cells are of the same type.…”

“…Outcomes in figure 7D are more complex than summarized. 2 Nicotine, in first place, decreases the amount of bursts to 3 vs 4, which subsequently increases the number of regular spikes. Besides, the time scale for figure 7Db,C are different, thereby effects are dramatized.…”

“…Although sometimes it is considered as a weak bursting, 7 a double-spiking shown in figure 1Ab is not an intrinsic burst (IB) firing. 2 A clear-cut bursting occurs spontaneously and is observed during longer recordings at the resting membrane potential (RMP). 8 Besides, the recorded phenotypes are not of typical pyramidal neurons within the subiculum (Figure 1A).…”