Neuromodulation of neurons and synapses
Introduction
The current understanding of nervous system function holds a prominent place for the role of neuromodulators in shaping electrophysiological activity. All nervous system function, from simple reflexes to sleep, memory and higher cognitive tasks, ultimately result from the activity of neural circuits. A wide variety of substances, including small molecule transmitters, biogenic amines, neuropeptides and others can be released in modes other than classical fast synaptic transmission, and modify neural circuit output to produce extensive adaptability in behaviors [1]. They do so by changing the properties of a circuit's constituent neurons, their synaptic connections or the inputs to the circuit. Such functional reconfiguration of hard-wired circuits is essential for the adaptability of the nervous system.
Neuromodulators are often thought to convey global control of brain states that underlie different behaviors, such as sleep and arousal. Implicit in this view is that one or a few modulators can dominate the operation of a large number of neurons and interconnected circuits, and that the global presence or absence of a neuromodulator is equivalent to a specific behavioral state. However, this view appears to contradict studies at the cellular level which show that multiple neuromodulators can act simultaneously on any single neuron, that intrinsic excitability and synaptic efficacy are always under neuromodulatory influence and, therefore, reconfiguration of neural circuits by neuromodulators is an intricately balanced process that involves multiple synergistic or antagonistic pathways. These conflicting views do not arise from contradictory experimental results, but rather from the challenge to bridge multiple levels of analysis from cellular to circuit to behavior. A comprehensive description of the variety of neuromodulator actions at these different levels is beyond the scope of a single review. Here we summarize findings that highlight the diversity of neuromodulatory effects on cellular and synaptic properties and discuss them in the context of local circuit activity.
Section snippets
Neuromodulation of synapses
Neuromodulators modify synaptic communication through a number of mechanisms which can be broadly divided into effects that target synapses directly and those that indirectly modify synaptic interactions by changing the excitability of neurons. Indirect effects include presynaptic modulation that can lead to changes in action potential shape [2, 3, 4••], and postsynaptic modulation that for example increases voltage-gated inward currents to enhance EPSPs [5, 6, 7•]. We will discuss these
Neuromodulation of synaptic strength
The simplest functional consequence of synapse modulation is the modification of synaptic strength. Multiple modulators can act on the same synapse to modify its strength, presumably depending on the behavioral need [24, 25]. Such effects can be drastic: 5-HT can functionally silence synapses in the crustacean stomatogastric ganglion (STG), whereas dopamine can unmask synapses that are normally silent [26]. The combined action of multiple neuromodulators on synapses can be more than simply
Neuromodulation of synaptic dynamics
In many systems, neuromodulators also act on synaptic dynamics (short-term synaptic plasticity, STP) [30, 44, 45, 46]. The effect of modulators can be drastic and in some cases can switch the sign of synaptic dynamics from depression to facilitation [33•, 47, 48, 49]. If the presynaptic neuron is active repetitively, STP can act as a gain-control mechanism, modifying synaptic strength as a function of the frequency of presynaptic activity [50, 51]. The modulation of STP can therefore be as
Neuromodulation of neuronal excitability
Responses to synaptic input, as well as spontaneous activity, critically depend on input conductance and the complement of voltage-gated currents. Differences in these properties across and within cell types can be due to differences in the types and spatial distribution of ion channels [68], in their relative expression levels [69], or in the gating properties of similar channels [70]. Accordingly, neuromodulators can change activity and excitability by adding or subtracting ionic currents,
From cellular and synaptic properties to circuit function
The modulation of neural circuits depends on the type, location and temporal dynamics of neuromodulator release [116]. The examples discussed above show that even a single neuromodulator can have complex effects on ion channels in each cell and on the strength and dynamics of synapses and, therefore, its effect on circuit output is not straightforward.
Changes in excitability are not always unequivocal. In the simplest case, a neuron's firing response to presynaptic activity increases or
Summary and conclusions
Neuromodulators target ion channels and synaptic interactions to modify circuit dynamics, which allows for adaptability of circuit operation in different behavioral contexts. Synaptic modulation is not limited to changes in the strength of connections, but involves modifications of short-term and long-term synaptic plasticity. Similarly, neuromodulation of intrinsic excitability is not limited to simple amplification or reduction of responsiveness to input, but can shape the nonlinear
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Isabel Soffer, Diana Martinez and Jorge Golowasch for their helpful comments. This work was supported in part by NIH grants NS083319 and MH060605.
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