Acetylcholine release inhibits distinct excitatory inputs onto hippocampal CA1 pyramidal neurons via different cellular and network mechanisms

Goswamee, Priyodarshan; McQuiston, A. Rory

doi:10.1101/575811

Cited by 3 publications

(6 citation statements)

References 49 publications

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“…1F-H; SC pathway 116 ± 8%, n = 6 from 3 mice, p > 0.05; TA pathway 106 ± 15%, n = 6 from 3 mice, p > 0.05). Therefore, contrary to our initial hypothesis 10,20,21,28 , acetylcholine did not inhibit one pathway more than the other but instead depressed both equally. We next tested disynaptic feedforward inhibitory post-synaptic currents (IPSCs) in response to stimulation of SC or TA pathways.…”

Section: Resultscontrasting

confidence: 99%

“…This agrees with the observed highly laminar localisation of M 3 receptors in the Stratum Lacunosum Moleculare, M 4 receptors in Stratum Radiatum and M 2 receptors in the Stratum Pyramidale 51 (but see ref. 28 ). At each terminal, muscarinic receptors depress neurotransmitter release probability 27,29,33,51 and we show that this includes M 3 receptors in the TA pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The anatomical segregation of TA and SC inputs to distal and more proximal dendritic locations on CA1 pyramidal neurons, respectively 25 , together with muscarinic receptor specificity provide potential mechanisms for differential sensitivity to acetylcholine and therefore altering the relative weights of synaptic input. However, the evidence for this is equivocal with exogenously applied cholinergic agonists indicating that SC transmission is more sensitive to cholinergic modulation than TA transmission 21 but the reverse reported for endogenous synaptically released acetylcholine 28 .…”

mentioning

confidence: 98%

“…Perhaps counter-intuitively, acetylcholine inhibits both TA and SC glutamatergic excitatory transmission in CA1. In the SC pathway, this occurs via presynaptic muscarinic M 4 receptors but the identity of the receptors mediating depression at the TA pathway is unclear [27][28][29] . The anatomical segregation of TA and SC inputs to distal and more proximal dendritic locations on CA1 pyramidal neurons, respectively 25 , together with muscarinic receptor specificity provide potential mechanisms for differential sensitivity to acetylcholine and therefore altering the relative weights of synaptic input.…”

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confidence: 99%

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Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

et al. 2021

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Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.

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Section: Resultscontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 98%

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Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

et al. 2021

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“…The optogenetic revolution has generated tools to manipulate circuits with precision and neurochemical selectivity, which is refining our views of circuit function. Optogenetic stimulation of cholinergic MS/DBB terminals decreased the pairedpulse ratio evoked by electrical stimulation in the stratum radiatum and increased that evoked by stimulation in the stratum lacunosum/moleculare, and both effects were mediated by muscarinic receptors: M2 and M3 receptors, respectively (Goswamee and McQuiston, 2019). Because the paired-pulse ratio is thought to be inversely related to presynaptic transmitter release, the interpretation of these results was that the MS/DBB cholinergic input directly inhibited presynaptic transmission in the stratum lacunosum/moleculare, but optogenetic stimulation of the same input indirectly inhibited transmission in the stratum radiatum through GABA interneurons acting on GABAB receptors and opening of GIRK channels on CA1 pyramidal cells.…”

Section: Physiologic Relevancementioning

confidence: 91%

Presynaptic Inhibitory Effects of Acetylcholine in the Hippocampus: A 40-Year Evolution of a Serendipitous Finding

Valentino

Dingledine

2021

J. Neurosci.

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Cholinergic regulation of hippocampal circuit activity has been an active area of neurophysiological research for decades. The prominent cholinergic innervation of intrinsic hippocampal circuitry, potent effects of cholinomimetic drugs, and behavioral responses to cholinergic modulation of hippocampal circuitry have driven investigators to discover diverse cellular actions of acetylcholine in distinct sites within hippocampal circuitry. Further research has illuminated how these actions organize circuit activity to optimize encoding of new information, promote consolidation, and coordinate this with recall of prior memories. The development of the hippocampal slice preparation was a major advance that accelerated knowledge of how hippocampal circuits functioned and how acetylcholine modulated these circuits. Using this preparation in the early 1980s, we made a serendipitous finding of a novel presynaptic inhibitory effect of acetylcholine on Schaffer collaterals, the projections from CA3 pyramidal neurons to dendrites of CA1 pyramidal cells. We characterized this effect at cellular and pharmacological levels, published the findings in the first volume of the Journal of Neuroscience, and proceeded to pursue other scientific directions. We were surprised and thrilled to see that, nearly 40 years later, the paper is still being cited and downloaded because the data became an integral piece of the foundation of the science of cholinergic regulation of hippocampal function in learning and memory. This Progressions article is a story of how single laboratory findings evolve through time to be confirmed, challenged, and reinterpreted by other laboratories to eventually become part of the basis of fundamental concepts related to important brain functions.

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Differential regulation of prelimbic and thalamic transmission to the basolateral amygdala by acetylcholine receptors

Tryon

Bratsch-Prince

Warren

et al. 2021

Preprint

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The amygdalar anterior basolateral nucleus (BLa) plays a vital role in emotional behaviors. This region receives dense cholinergic projections from basal forebrain which are critical in regulating neuronal activity and synaptic transmission. Cholinergic signaling in BLa is thought to occur through both a slow mode of volume transmission as well as a rapid, phasic mode. However, the relative effect of each mode of signaling in BLa is not understood. Here, we used electrophysiology and optogenetics in mouse brain slices to compare regulation of afferent input from cortex and thalamus to the BLa by these two modes of transmission. Phasic ACh release evoked by single pulse stimulation of cholinergic terminals had a biphasic effect on glutamatergic transmission at cortical input, producing rapid nicotinic receptor-mediated facilitation followed by slower muscarinic receptor (mAChR)-mediated depression. In contrast, tonic elevation of ACh through application of the cholinesterase inhibitor physostigmine suppressed glutamatergic transmission at cortical inputs through mAChRs only. This suppression was not observed at thalamic inputs to BLa. In agreement with this pathway-specificity, the mAChR agonist, muscarine more potently suppressed transmission at inputs from prelimbic cortex (PL) than thalamus. Muscarinic inhibition at PL input was dependent on presynaptic M4 mAChRs, while at thalamic input it depended upon M3 mAChR-mediated stimulation of retrograde endocannabinoid signaling. Muscarinic inhibition at both pathways was frequency-dependent, allowing only high frequency activity to pass. These findings demonstrate complex cholinergic regulation of afferent input to BLa that depends upon the mode of ACh release and is both pathway specific and frequency dependent.

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Acetylcholine release inhibits distinct excitatory inputs onto hippocampal CA1 pyramidal neurons via different cellular and network mechanisms

Cited by 3 publications

References 49 publications

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

Presynaptic Inhibitory Effects of Acetylcholine in the Hippocampus: A 40-Year Evolution of a Serendipitous Finding

Differential regulation of prelimbic and thalamic transmission to the basolateral amygdala by acetylcholine receptors

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