Cholinergic Coordination of Presynaptic and Postsynaptic Activity Induces Timing-Dependent Hippocampal Synaptic Plasticity

Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2012; 32(36):12337-48. DOI: 10.1523/JNEUROSCI.2129-12.2012
Source: PubMed


Correlated presynaptic and postsynaptic activity is the key factor in inducing Hebbian plasticity and memory. However, little is known about the physiological events that could mediate such coordination. Correlated cholinergic input induces spike timing-dependent plasticity-like hippocampal synaptic plasticity. Cholinergic receptors are localized to both presynaptic and postsynaptic glutamatergic sites and thus have the potential to coordinate presynaptic and postsynaptic activity to induce plasticity. By directly monitoring presynaptic and postsynaptic activities with genetically encoded calcium indicators in mouse septohippocampal cocultures, we found interactive but independent presynaptic and postsynaptic modulations in the cholinergic-dependent synaptic plasticity. Neither presynaptic nor postsynaptic modulation alone is sufficient, but instead a coordinated modulation at both sites is required to induce the plasticity. Therefore, we propose that correlated cholinergic input can coordinate presynaptic and postsynaptic activities to induce timing-dependent synaptic plasticity, providing a novel mechanism by which neuromodulators precisely modulate network activity and plasticity with high efficiency and temporal precision.

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    • "Among the most abundant nAChRs are homopentameric α7-containing receptors (α7-nAChRs), which can be located both pre-and postsynaptically at many kinds of central synapses. The receptors can mediate synaptic plasticity; even brief activation of α7-nAChRs can induce long-term potentiation (LTP; Fuiji et al., 1999; Gu et al., 2012; Ji et al., 2001; Kenney and Gould, 2008; Placzek et al., 2009; Yakel, 2012). A common mechanism driving long-term synaptic plasticity is a change in the number or functionality of postsynaptic glutamate receptors at a glutamatergic synapse (Bear and Abraham, 1996; Bliss and Collingridge, 1993; Derkach et al., 2007; Lau and Zukin, 2007). "
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    ABSTRACT: Cholinergic neurons project throughout the nervous system and activate nicotinic receptors to modulate synaptic function in ways that shape higher order brain function. The acute effects of nicotinic signaling on long-term synaptic plasticity have been well-characterized. Less well understood is how chronic exposure to low levels of nicotine, such as those encountered by habitual smokers, can alter neural connections to promote addiction and other lasting behavioral effects. We show here that chronic exposure of hippocampal neurons in culture to low levels of nicotine recruits AMPA and NMDA receptors to the cell surface and sequesters them at postsynaptic sites. The receptors include GluA2-containing AMPA receptors, which are responsible for most of the excitatory postsynaptic current mediated by AMPA receptors on the neurons, and include NMDA receptors containing GluN1 and GluN2B subunits. Moreover, we find that the nicotine treatment also increases expression of the presynaptic component synapsin 1 and arranges it in puncta juxtaposed to the additional AMPA and NMDA receptor puncta, suggestive of increases in synaptic contacts. Consistent with increased synaptic input, we find that the nicotine treatment leads to an increase in the excitatory postsynaptic currents mediated by AMPA and NMDA receptors. Further, the increases skew the ratio of excitatory-to-inhibitory input that the cell receives, and this holds both for pyramidal neurons and inhibitory neurons in the hippocampal CA1 region. The GluN2B-containing NMDA receptor redistribution at synapses is associated with a significant increase in GluN2B phosphorylation at Tyr1472, a site known to prevent GluN2B endocytosis. These results suggest that chronic exposure to low levels of nicotine not only alters functional connections but also is likely to change excitability levels across networks. Further, it may increase the propensity for synaptic plasticity, given the increase in synaptic NMDA receptors.
    Molecular and Cellular Neuroscience 09/2015; 68. DOI:10.1016/j.mcn.2015.09.002 · 3.84 Impact Factor
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    • "There are two types of AChRs: the nAChR and mAChR. Both receptors allow ACh to change the electrical activity of the target cells and to affect other processes through intracellular signaling cascades (Dajas-Bailador and Wonnacott, 2004; Gulledge and Stuart, 2005; Intskirveli and Metherate, 2012; Thiele, 2013; Yakel, 2013). However, these receptors function in fundamentally different ways. "
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    ABSTRACT: Acetylcholine (ACh) release in the medial prefrontal cortex (mPFC) is crucial for normal cognitive performance. Despite the fact that many have studied how ACh affects neuronal processing in the mPFC and thereby influences attention behavior, there is still a lot unknown about how this occurs. Here we will review the evidence that cholinergic modulation of the mPFC plays a role in attention and we will summarize the current knowledge about the role between ACh receptors (AChRs) and behavior and how ACh receptor activation changes processing in the cortical microcircuitry. Recent evidence implicates fast phasic release of ACh in cue detection and attention. This review will focus mainly on the fast ionotropic nicotinic receptors and less on the metabotropic muscarinic receptors. Finally, we will review limitations of the existing studies and address how innovative technologies might push the field forward in order to gain understanding into the relation between ACh, neuronal activity and behavior.
    Frontiers in Neural Circuits 03/2014; 8:17. DOI:10.3389/fncir.2014.00017 · 3.60 Impact Factor
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    • "As well as directly causing short- and long-term synaptic plasticity, cholinergic receptor activation modulates the induction of synaptic plasticity (Shimoshige et al., 1997; Leung et al., 2003; Ovsepian et al., 2004; Ge and Dani, 2005; Shinoe et al., 2005). The precise mechanism and direction of modulation may depend on acetylcholine concentration, the timing of its release, exposure time and the temporal sequence of nAChRs and mAChRs activation in relation to ongoing neuronal activity (Fujii and Sumikawa, 2001; Ge and Dani, 2005; Gu and Yakel, 2011; Gu et al., 2012). A number of mechanisms have been proposed for the modulation of synaptic plasticity. "
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    ABSTRACT: Cholinergic septohippocampal projections from the medial septal area to the hippocampus are proposed to have important roles in cognition by modulating properties of the hippocampal network. However, the precise spatial and temporal profile of acetylcholine release in the hippocampus remains unclear making it difficult to define specific roles for cholinergic transmission in hippocampal dependent behaviors. This is partly due to a lack of tools enabling specific intervention in, and recording of, cholinergic transmission. Here, we review the organization of septohippocampal cholinergic projections and hippocampal acetylcholine receptors as well as the role of cholinergic transmission in modulating cellular excitability, synaptic plasticity, and rhythmic network oscillations. We point to a number of open questions that remain unanswered and discuss the potential for recently developed techniques to provide a radical reappraisal of the function of cholinergic inputs to the hippocampus.
    Frontiers in Synaptic Neuroscience 07/2013; 5:2. DOI:10.3389/fnsyn.2013.00002
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