Why is acetylcholine released

Although cholinergic receptors have been shown to affect inhibitory presynaptic terminals Behrends and Ten Bruggencate, ; Tang et al. The impact that acetylcholine release has in hippocampal CA1 and the extent to which different interneuron subtypes are affected will depend on the specific location and density of cholinergic axon terminals as well as its inactivating enzyme, acetylcholinesterase. Notably, both cholinergic fibers and acetylcholinesterase have been shown to be differentially distributed across layers in hippocampal CA1.

In mouse, cholinergic fibers were shown to be evenly distributed except for two bands of higher density in the stratum pyamidale SP and at the border between the stratum radiatum SR and stratum lacunosum-moleculare SLM Aznavour et al. Consistent with these anatomical data, measurements of increased acetylcholine release during theta rhythms have shown that acetylcholine concentrations were highest near the stratum pyramidale Zhang et al.

This differential distribution of cholinergic fibers and extracellular acetylcholine levels is particularly important when considering that not all cholinergic terminals in the hippocampus appear to transmit acetylcholine synaptically. Regardless of this discrepancy, a significant portion of terminals appear to release acetylcholine into the extracellular space in a paracrine-like manner. This requires terminally released acetylcholine to diffuse significant distances past acetylcholinesterase to bind to receptors on postsynaptic elements.

Furthermore, it is possible that there is a subset of terminals that are more active, have a higher probability of release, or may release more neurotransmitter. These terminals may be more effective at mediating volume transmission and influencing nearby inhibitory interneurons.

Nevertheless, potential differences in the firing frequency or the duration of activity of cholinergic neurons could have variable effects on different interneuron subtypes through local differences in acetylcholine concentrations. A potential role for inhibitory interneurons in muscarinic receptor modulation of hippocampal function was initially based on observations that the exogenous application of cholinergic agonists resulted in an increase in spontaneous inhibitory postsynaptic currents sIPSCs in CA1 pyramidal neurons Pitler and Alger, These data indirectly suggested that a subset of inhibitory interneurons may be depolarized by muscarinic receptor activation and were subsequently confirmed by direct recordings Parra et al.

However, not all interneurons responded to muscarinic receptor activation by depolarizing. Some interneurons were hyperpolarized or exhibited biphasic responses, and some failed to respond to the exogenous application of muscarinic agonist Parra et al.

Moreover, each muscarinic response type could not be correlated with a morphological subtype of interneuron. These findings were further complicated by the observation that muscarinic receptors can inhibit the release of GABA from a subset of perisomatic inhibitory interneurons Behrends and Ten Bruggencate, ; Fukudome et al.

Thus, the impact that acetylcholine release has on the interneuron population is complex and results in the recruitment of some interneurons while inhibiting others. Although cholinergic muscarinic synaptic responses were first measured in CA1 pyramidal neurons in Cole and Nicoll, , it was not until that muscarinic responses to electrically evoked acetylcholine release were measured in hippocampal CA1 inhibitory interneurons Widmer et al.

This study showed that terminally released acetylcholine had divergent effects on different interneuron subtypes. Interneurons could respond by depolarizing, hyperpolarizing, or with biphasic responses.

Moreover, like previous studies using exogenous application of muscarinic agonists Parra et al. These findings have been recently confirmed by optogenetic studies using evoked release in response to light-activation Nagode et al. Furthermore, the muscarinic hyperpolarizations were mediated by the activation of M 4 receptors whereas the depolarizations were likely produced by M 3 receptor activation Bell et al.

Similar to the electrical stimulation studies, muscarinic response type could not be correlated with anatomical interneuron subtypes. Importantly, both studies showed that perisomatically projecting interneurons likely parvalbumin-expressing basket cells could respond to acetylcholine release with any one of the three muscarinic response types Widmer et al.

Optogenetically released acetylcholine resulted in an increase in large amplitude sIPSCs with frequencies that fell within the theta bandwidth 4—12 Hz Nagode et al.

Importantly, this increase in sIPSCs could be inhibited by endocannabinoids suggesting that they resulted from the activation of cholecystokinin positive interneurons Nagode et al. Furthermore, the sIPSCs were not affected by optogenetic suppression of parvalbumin positive cells, suggesting they did not arise from the activation of parvalbumin basket cells, axo-axonic, bistratified or oriens-lacunosum-moleculare interneurons Nagode et al.

These findings are consistent with synaptic stimulation studies, which recorded from an interneuron with cholecystokinin basket cell morphology that produced a biphasic response to acetylcholine release Widmer et al.

Therefore, based on effects on the membrane potential alone, endogenously activated muscarinic receptors on hippocampal CA1 interneurons will have complex effects on network function see Table 1. Table 1. Cholinergic responses vary in similar and different anatomical interneuron subtypes. Although different muscarinic response types were almost uniformly observed in CA1 interneurons, not all response types were as easily evoked by optogenetic stimulation Bell et al.

However, the number of flashes affected the probability of observing a particular response type. Activation of nicotinic receptors in the hippocampus has a significant impact on physiological and pathophysiological memory formation Levin, ; Levin et al.

Of the 11 different nicotinic receptor subunits found in the mammalian CNS, 9 have been reported to be expressed in hippocampal CA1 neurons Sudweeks and Yakel, To fully understand the role that different nicotinic subunits play in the hippocampus, the effect of endogenously released acetylcholine on individual hippocampal cells and the hippocampal network has begun to be investigated.

Nicotinic excitatory postsynaptic currents EPSCs were first observed using electrical stimulation and whole cell patch clamping in acute rat brain slices. However, more recent optogenetic studies in mouse brain slices were not able to reproduce these earlier observations Bell et al. Although these small nicotinic responses could temporally summate, their ability to excite interneurons was limited through muscarinic presynaptic inhibition.

Because the nicotinic responses were mostly subthreshold, nicotinic transmission onto CA1 interneurons may be primarily modulatory in nature. The optogenetic studies also examined the nicotinic responses using voltage-sensitive dye VSD imaging. Notably, nicotinic responses could be produced by a single flash of light Bell et al.

Because CA1 inhibitory interneuron membrane potentials can be differentially modulated by both muscarinic and nicotinic receptor activation following acetylcholine release, the consequential effect on network function is undoubtedly complex. Muscarinic receptor activation can result in varying and opposing effects, even within the same interneuron see Table 1.

Unfortunately, our understanding of how each subtype of interneuron can be affected by muscarinic or nicotinic receptor activation remains incomplete.

Nevertheless, the number of stimuli required to produce each type of response varied in a consistent manner. Nicotinic responses were most easily evoked requiring the fewest number of stimuli Bell et al. Furthermore, postulating that nicotinic responses preferentially affect interneurons that selectively inhibit other interneurons interneuron-selective or IS , nicotinic receptor activation may also result in disinhibition of CA1 pyramidal neurons Figure 1A.

Increased output from CA1 may result in the facilitation of recall and memory consolidation in other areas of the CNS as is thought to occur during slow wave sleep Gais and Born, ; Hasselmo and McGaughy, Some of these depolarizing interneurons may impose rhythmic inhibition of CA1 pyramidal neurons at theta frequencies Nagode et al.

This would result in inhibition of hippocampal CA1 pyramidal neuron output partly rhythmic while facilitating synaptic integration within hippocampal CA1 pyramidal cell dendrites through cholinergic effects on glutamatergic receptors and dendritic function Figure 1C Tsubokawa and Ross, ; Tsubokawa, ; Fernandez De Sevilla and Buno, ; Giessel and Sabatini, Indeed, such a dynamic role for acetylcholine concentrations in learning and memory formation has been previously proposed Hasselmo, ; Hasselmo and Giocomo, ; Giocomo and Hasselmo, ; Hasselmo and Sarter, In this scheme, lower acetylcholine concentrations permit intrahippocampal Schaffer collaterals synaptic interactions to dominate thus increasing hippocampal CA1 output and memory retrieval, whereas higher acetylcholine concentrations favor processing of inputs from outside the hippocampus permitting the transient formation of memories in hippocampal CA1.

Therefore, the combined effect of acetylcholine release on glutamatergic inputs and interneuron function may play important roles in tuning the hippocampal CA1 network for recall or to form new memories. Figure 1. We postulate that nicotinic-driven interneurons are interneurons-selective interneurons IS, yellow—activation that specifically inhibit other interneurons blue.

Increasing their activity results in disinhibition of pyramidal neurons P, yellow—activation, and increased output. C Increasing cholinergic neuron activity causes subsets of interneurons to be depolarized by muscarinic receptor activation I, red—activation, and increased synaptic inhibition resulting in suppression of pyramidal neurons P, blue—suppressed output.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Adler, L. Schizophrenia, sensory gating, and nicotinic receptors.

Alkondon, M. Brain Res. Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices. Pubmed Abstract Pubmed Full Text. Atri, A. Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task. Aznavour, N. Comparative analysis of cholinergic innervation in the dorsal hippocampus of adult mouse and rat: a quantitative immunocytochemical study.

Hippocampus 12, — Barrenechea, C. In vivo intracellular recordings of medial septal and diagonal band of Broca neurons: relationships with theta rhythm. Behrends, J. Cholinergic modulation of synaptic inhibition in the guinea pig hippocampus in vitro : excitation of GABAergic interneurons and inhibition of GABA-release.

Bell, K. Nicotinic excitatory postsynaptic potentials in hippocampal CA1 interneurons are predominantly mediated by nicotinic receptors that contain alpha4 and beta2 subunits. Neuropharmacology 61, — Bell, L. Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes. Neuropharmacology 73, — Sam C, Bordoni B. Physiology, acetylcholine. In: StatPearls. StatPearls Publishing; The Nobel Prize.

Sir Henry Dale - facts. Lombardo S, Maskos U. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr Neuropharmacol. Your Privacy Rights.

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Related Articles. No useful pharmacological agents are available to modify cholinergic function through interaction with the storage of ACh. Interestingly, the gene for VAChT is contained on the first intron of the choline acetyltransferase gene. This proximity implies the two important cholinergic proteins are probably regulated coordinately. You will recall that the miniature endplate potentials and the quantal release in response to action potentials at the neuromuscular junction are due to the release of packets of ACh from individual storage vesicles Chapter 5.

Many toxins are known that interfere with these processes and are effective in preventing ACh secretion. The examples in Figure There are two broad classes of cholinergic receptors: nicotinic and muscarinic. This classification is based on two chemical agents that mimic the effects of ACh at the receptor site nicotine and muscarine.

ACh binds to the two a subunits. The bottom half shows the molecular structure of each a subunit of the nicotinic receptor based on cDNA derived amino acid sequence. A funnel-shaped internal ion channel is surrounded by the five subunits.

Muscarinic receptors, classified as G protein coupled receptors GPCR , are located at parasympathetic autonomically innervated visceral organs, on the sweat glands and piloerector muscles and both post-synaptically and pre-synaptically in the CNS see Table I. The muscarinic receptor is composed of a single polypeptide. Because each of these regions of the protein is markedly hydrophobic, they span the cell membrane seven times as depicted in Figure The fifth internal loop and the carboxyl-terminal tail of the polypeptide receptor are believed to be the site of the interaction of the muscarinic receptor with G proteins see right.

The site of agonist binding is a circular pocket formed by the upper portions of the seven membrane-spanning regions. ACh has excitatory actions at the neuromuscular junction, at autonomic ganglion, at certain glandular tissues and in the CNS. It has inhibitory actions at certain smooth muscles and at cardiac muscle.

The biochemical responses to stimulation of muscarinic receptor involve the receptor occupancy causing an altered conformation of an associated GTP-binding protein G protein. In response to the altered conformation of the muscarinic receptor, the a subunit of the G protein releases bound guanosine diphosphate GDP and simultaneously binds guanosine triphosphate GTP.

This hydrolysis terminates the action of the G protein. The rate of hydrolysis of the GTP thus dictates the length of time the G protein remains activated. Inhibition of Adenylate Cyclase: The muscarinic receptor, through interaction with an inhibitory GTP-binding protein, acts to inhibit adenylyl cyclase. Reduced cAMP production leads to reduced activation of cAMP-dependent protein kinase , reduced heart rate, and contraction strength.

As shown in Figure The DAG activates protein kinase C not shown. Cellular responses are influenced by PKC's phosphorylation of target proteins. This conductance increase increases the resting membrane potential in myocardial and other cell membranes leading to inhibition.

ACh binds only briefly to the pre- or postsynaptic receptors. Following dissociation from the receptor, the ACh is rapidly hydrolyzed by the enzyme acetylcholinesterase AChE as shown in Figure This enzyme has a very high catalysis rate, one of the highest known in biology. AChE is synthesized in the neuronal cell body and distributed throughout the neuron by axoplasmic transport. AChE exists as alternatively spliced isoforms that vary in their subunit composition.

The variation at the NMJ is a heteromeric protein composed of four subunits coupled to a collagen tail that anchors the multi-subunit enzyme to the cell membrane of the postsynaptic cell Figure This four-subunit form is held together by sulfhydryl bonds and the tail anchors the enzyme in the extracellular matrix at the NMJ.

Other isoforms are homomeric and freely soluble in the cytoplasm of the presynaptic cell. In addition, other cholinesterases exist throughout the body, which are also able to metabolize acetylcholine. These are termed pseudocholinesterases.