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Review
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Neuromodulators and Long-Term Synaptic Plasticity in Learning and Memory: A Steered-Glutamatergic Perspective

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Review

Neuromodulators and Long-Term Synaptic Plasticity in Learning and Memory: A Steered-Glutamatergic Perspective

Amjad H Bazzari et al. Brain Sci.

Abstract

The molecular pathways underlying the induction and maintenance of long-term synaptic plasticity have been extensively investigated revealing various mechanisms by which neurons control their synaptic strength. The dynamic nature of neuronal connections combined with plasticity-mediated long-lasting structural and functional alterations provide valuable insights into neuronal encoding processes as molecular substrates of not only learning and memory but potentially other sensory, motor and behavioural functions that reflect previous experience. However, one key element receiving little attention in the study of synaptic plasticity is the role of neuromodulators, which are known to orchestrate neuronal activity on brain-wide, network and synaptic scales. We aim to review current evidence on the mechanisms by which certain modulators, namely dopamine, acetylcholine, noradrenaline and serotonin, control synaptic plasticity induction through corresponding metabotropic receptors in a pathway-specific manner. Lastly, we propose that neuromodulators control plasticity outcomes through steering glutamatergic transmission, thereby gating its induction and maintenance.

Keywords: GPCR; LTD; LTP; astrocytes; learning; memory; neuromodulators; synaptic plasticity.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the main metabotropic signalling pathways by which neuromodulators control long-term potentiation (LTP). Neuromodulators activate various protein kinases that can: Firstly, modulate neuronal excitability through controlling ion-channel conductance (e.g., NMDAR and VGCC) leading to the facilitation or direct induction of LTP. Secondly, protein kinases (e.g., PKA, MAPK and PKC) can initiate the expression, trafficking, phosphorylation and/or synaptic insertion of AMPA receptors leading to LTP expression. Lastly, protein kinases trigger the gene expression of proteins necessary for LTP maintenance. * It is also implicated in long-term depression (LTD), mostly through AMPA receptor internalisation.
Figure 2
Figure 2
A schematic representation of astrocytic synaptic coverage and neuromodulatory inputs. Astrocytes are able to detect and respond to both synaptic activity and neuromodulatory afferent signals. Neuromodulators and neuron-released transmitters (presynaptic and postsynaptic retrograde messengers) activate associated receptors on perisynaptic astrocyte processes leading to intracellular calcium signalling and subsequent induction of gliotransmitter release to modulate local activity and synaptic plasticity. Similarly, neuromodulatory signals can target neurons, astrocytes or both; hence, neuromodulators transmit behaviour-related signals to induce neuronal activity directly and/or through astrocytes.
Figure 3
Figure 3
A model of behaviour-dependent neuromodulation of synaptic plasticity. Tonic release of neuromodulators controls baseline and task-induced levels which mediate attention. The cooperative actions of tonic and phasic release during learning tasks modulate network activity and neuronal oscillations that prime plasticity induction through functional coupling, pathway selection and signal amplification. Salient stimuli such as unexpected novelty and reward cues (in rodent models) trigger sub-second phasic transmission to provide the induction/maintenance signal provided that background/tonic levels are “appropriate” for induction. * Salient stimulus.

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