Abstract
Acetylcholine (ACh) release onto nicotinic receptors directly activates subsets of inhibitory interneurons in hippocampal CA1. However, the specific interneurons activated and their effect on the hippocampal network is not completely understood. Therefore, we investigated subsets of hippocampal CA1 interneurons that respond to ACh release through the activation of nicotinic receptors and the potential downstream effects this may have on hippocampal CA1 network function. ACh was optogenetically released in mouse hippocampal slices by expressing the excitatory optogenetic protein oChIEF-tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated viral mediated transfection. The actions of optogenetically released ACh were assessed on both pyramidal neurons and different interneuron subtypes via whole cell patch clamp methods. Vasoactive intestinal peptide (VIP)-expressing interneurons that selectively innervate other interneurons (VIP/IS) were excited by ACh through the activation of nicotinic receptors containing α4 and β2 subunits (α4β2*). ACh release onto VIP/IS was presynaptically inhibited by M2 muscarinic autoreceptors. ACh release produced spontaneous inhibitory postsynaptic current (sIPSC) barrages blocked by dihydro-β-erythroidine in interneurons but not pyramidal neurons. Optogenetic suppression of VIP interneurons did not inhibit these sIPSC barrages suggesting other interneuron-selective interneurons were also excited by α4β2* nicotinic receptor activation. In contrast, interneurons that innervate pyramidal neuron perisomatic regions were not activated by ACh release onto nicotinic receptors. Therefore, we propose ACh release in CA1 facilitates disinhibition through activation of α4β2* nicotinic receptors on interneuron-selective interneurons whereas interneurons that innervate pyramidal neurons are less affected by nicotinic receptor activation.
Highlights
The formation of new memories in the hippocampus is influenced by nicotinic receptor function
ACh Released from medial septum/diagonal band of Broca (MS/DBB) Terminals Selectively Produced α4β2∗ Nicotinic Responses in Vasoactive intestinal peptide (VIP) Interneuron-Selective Interneurons There are two types interneurons that express vasoactiveintestinal peptide (VIP) in hippocampal CA1: those that exclusively innervate other interneurons and those that innervate the perisomatic region of pyramidal neurons (VIP basket cells, VIP/BC) (Acsády et al, 1996b)
While nicotinic responses appear to occur in neocortical VIP interneurons (Arroyo et al, 2012), little is known about how hippocampal VIP interneurons respond to ACh released from MS/DBB cholinergic terminals
Summary
The formation of new memories in the hippocampus is influenced by nicotinic receptor function. Nicotinic transmission onto CA1 interneurons and memory performance can be impaired by the injection of α4β2∗ (nicotinic receptors that contain α4 and β2 subunits but may include other types of subunits) or α7 nicotinic receptor antagonists directly into the hippocampus (Levin, 2002) Dysfunction of both α4 and β2 nicotinic subunits in the hippocampus have been correlated with memory impairment associated with addiction, neurodegenerative disease and aging. Beta amyloid protein, a protein that has been associated with the etiology of Alzheimer’s disease, can inhibit α4β2∗ receptors at low concentrations (Wu et al, 2004) It appears that α4β2∗ nicotinic receptor function in the hippocampus is necessary for normal memory formation and their dysfunction may contribute to memory impairment associated with aging and neurodegenerative disease
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