Abstract
The parasubiculum (PaS) is a component of the hippocampal formation that sends its major output to layer II of the entorhinal cortex. The PaS receives strong cholinergic innervation from the basal forebrain that is likely to modulate neuronal excitability and contribute to theta-frequency network activity. The present study used whole cell current- and voltage-clamp recordings to determine the effects of cholinergic receptor activation on layer II PaS neurons. Bath application of carbachol (CCh; 10–50 µM) resulted in a dose-dependent depolarization of morphologically-identified layer II stellate and pyramidal cells that was not prevented by blockade of excitatory and inhibitory synaptic inputs. Bath application of the M1 receptor antagonist pirenzepine (1 µM), but not the M2-preferring antagonist methoctramine (1 µM), blocked the depolarization, suggesting that it is dependent on M1 receptors. Voltage-clamp experiments using ramped voltage commands showed that CCh resulted in the gradual development of an inward current that was partially blocked by concurrent application of the selective Kv7.2/3 channel antagonist XE-991, which inhibits the muscarine-dependent K+ current I M. The remaining inward current also reversed near EK and was inhibited by the K+ channel blocker Ba2+, suggesting that M1 receptor activation attenuates both I M as well as an additional K+ current. The additional K+ current showed rectification at depolarized voltages, similar to K+ conductances mediated by Kir 2.3 channels. The cholinergic depolarization of layer II PaS neurons therefore appears to occur through M1-mediated effects on I M as well as an additional K+ conductance.
Highlights
Recent evidence suggests that the parasubiculum (PaS), which is a major component of the subicular complex, plays an important role within the brain navigational system [1,2,3]
The results presented here show that cholinergic receptor activation has a strong depolarizing effect on resting membrane potential in layer II PaS neurons, and this contrasts sharply with the powerful muscarinic suppression of excitatory synaptic transmission that we have observed previously [38]
The depolarization was found to be due to activation of M1 muscarinic receptors, and comparison of currents induced during slowly ramped voltage commands indicate that the muscarinic depolarization is mediated via inhibition of IM as well as an additional K+ current
Summary
Recent evidence suggests that the parasubiculum (PaS), which is a major component of the subicular complex, plays an important role within the brain navigational system [1,2,3]. We have recently shown that atropine-sensitive theta-frequency LFP activity is generated locally within the superficial layers of the PaS, and that layer II PaS neurons display theta-frequency oscillations in membrane potential at near-threshold voltages [11,12]. Septal cholinergic inputs may help to generate membrane potential oscillations by depolarizing PaS neurons to near-threshold voltages [13]. Cholinergic modulation of principal cell types in retrohippocampal cortices is likely to play an important role in encoding and retrieval processes associated with these regions [16,21], and it is crucial to understand how neuromodulators such as acetylcholine modulate the basic cellular properties of parasubicular neurons
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