Elsevier

Current Opinion in Neurobiology

Volume 29, December 2014, Pages 48-56
Current Opinion in Neurobiology

Neuromodulation of neurons and synapses

https://doi.org/10.1016/j.conb.2014.05.003Get rights and content

Highlights

  • Modulation of synaptic strength can occur through changes in short-term plasticity.

  • Modulators can shape or induce long-term synaptic plasticity.

  • Modulators can have spatially specific and divergent targets in single neurons.

  • Modulators can change neuronal excitability qualitatively and nonlinearly.

  • Classical ionotropic receptors can exert unambiguously modulatory effects.

Neuromodulation underlies the flexibility of neural circuit operation and behavior. Individual neuromodulators can have divergent actions in a neuron by targeting multiple physiological mechanisms. Conversely, multiple neuromodulators may have convergent actions through overlapping targets. The divergent and convergent neuromodulator actions can be unambiguously synergistic or antagonistic, but neuromodulation often entails balanced adjustment of nonlinear membrane and synaptic properties by targeting ion channel and synaptic dynamics rather than just excitability or synaptic strength. In addition, neuromodulators can exert effects at multiple timescales, from short-term adjustments of neuron and synapse function to persistent long-term regulation. This short review summarizes some highlights of the diverse actions of neuromodulators on ion channel and synaptic properties.

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.

References (124)

  • G.H. Seol et al.

    Neuromodulators control the polarity of spike-timing-dependent synaptic plasticity

    Neuron

    (2007)
  • Z. Nusser

    Variability in the subcellular distribution of ion channels increases neuronal diversity

    Trends Neurosci

    (2009)
  • A.A. Prinz et al.

    Alternative to hand-tuning conductance-based models: construction and analysis of databases of model neurons

    J Neurophysiol

    (2003)
  • C.L. Pfeiffer-Linn et al.

    Dopamine modulates unitary conductance of single PL-type calcium channels in Roccus chrysops retinal horizontal cells

    J Physiol

    (1996)
  • A.R. Cantrell et al.

    Neuromodulation of Na+ channels: an unexpected form of cellular plasticity

    Nat Rev Neurosci

    (2001)
  • F.J. Berendt et al.

    Multisite phosphorylation of voltage-gated sodium channel alpha subunits from rat brain

    J Proteome Res

    (2010)
  • R. Hourez et al.

    Activation of protein kinase C and inositol 1,4,5-triphosphate receptors antagonistically modulate voltage-gated sodium channels in striatal neurons

    Brain Res

    (2005)
  • A.M. Swensen et al.

    Multiple peptides converge to activate the same voltage-dependent current in a central pattern-generating circuit

    J Neurosci

    (2000)
  • A.M. Swensen et al.

    Modulators with convergent cellular actions elicit distinct circuit outputs

    J Neurosci

    (2001)
  • S. Gasparini et al.

    Phosphorylation-dependent differences in the activation properties of distal and proximal dendritic Na+ channels in rat CA1 hippocampal neurons

    J Physiol

    (2002)
  • J.E. Sirois et al.

    The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics

    J Neurosci

    (2000)
  • D. Bucher et al.

    SnapShot: neuromodulation

    Cell

    (2013)
  • S.C. Rosen et al.

    Selective modulation of spike duration by serotonin and the neuropeptides, FMRFamide, SCPB, buccalin and myomodulin in different classes of mechanoafferent neurons in the cerebral ganglion of Aplysia

    J Neurosci

    (1989)
  • A. Sakurai et al.

    Serotonergic enhancement of a 4-AP-sensitive current mediates the synaptic depression phase of spike timing-dependent neuromodulation

    J Neurosci

    (2006)
  • T. Sasaki et al.

    Action-potential modulation during axonal conduction

    Science

    (2011)
  • C.J. Heckman et al.

    Motoneuron excitability: the importance of neuromodulatory inputs

    Clin Neurophysiol

    (2009)
  • M.M. Rank et al.

    Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury

    J Neurophysiol

    (2010)
  • B.E. McKay et al.

    Regulation of synaptic transmission and plasticity by neuronal nicotinic acetylcholine receptors

    Biochem Pharmacol

    (2007)
  • M.J. Higley et al.

    Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors

    Nat Neurosci

    (2010)
  • S. Logsdon et al.

    Regulation of synaptic vesicles pools within motor nerve terminals during short-term facilitation and neuromodulation

    J Appl Physiol (1985)

    (2006)
  • J. Feng et al.

    Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons

    J Neurosci

    (2001)
  • M. Kano et al.

    Endocannabinoid-mediated control of synaptic transmission

    Physiol Rev

    (2009)
  • W.M. Fu et al.

    Nerve terminal currents induced by autoreception of acetylcholine release

    J Neurosci

    (1998)
  • L.N. Cui et al.

    GABA(B) presynaptically modulates suprachiasmatic input to hypothalamic paraventricular magnocellular neurons

    Am J Physiol Regul Integr Comp Physiol

    (2000)
  • S.Z. Langer

    Presynaptic autoreceptors regulating transmitter release

    Neurochem Int

    (2008)
  • A. Pinard et al.

    Nitric oxide dependence of glutamate-mediated modulation at a vertebrate neuromuscular junction

    Eur J Neurosci

    (2008)
  • J.A. Ribeiro et al.

    Modulation and metamodulation of synapses by adenosine

    Acta Physiol (Oxf)

    (2010)
  • P. Katz et al.

    Metamodulation: the control and modulation of neuromodulation

  • K.A. Mesce

    Metamodulation of the biogenic amines: second-order modulation by steroid hormones and amine cocktails

    Brain Behav Evol

    (2002)
  • V. Pawlak et al.

    Timing is not everything: neuromodulation opens the STDP gate

    Front Synaptic Neurosci

    (2010)
  • B.R. Johnson et al.

    Differential modulation of synaptic strength and timing regulate synaptic efficacy in a motor network

    J Neurophysiol

    (2011)
  • P.S. Katz et al.

    Dynamic neuromodulation of synaptic strength intrinsic to a central pattern generator circuit

    Nature

    (1994)
  • B.R. Johnson et al.

    Differential modulation of chemical and electrical components of mixed synapses in the lobster stomatogastric ganglion

    J Comp Physiol A

    (1994)
  • H.Y. Koh et al.

    Two neuropeptides colocalized in a command-like neuron use distinct mechanisms to enhance its fast synaptic connection

    J Neurophysiol

    (2003)
  • Z. Gu et al.

    Bidirectional regulation of Ca2+/calmodulin-dependent protein kinase II activity by dopamine D4 receptors in prefrontal cortex

    Mol Pharmacol

    (2004)
  • X. Cai et al.

    Activity-dependent bidirectional regulation of GABAA receptor channels by the 5-HT4 receptor-mediated signalling in rat prefrontal cortical pyramidal neurons

    J Physiol

    (2002)
  • A. Sakurai et al.

    State-, timing-, and pattern-dependent neuromodulation of synaptic strength by a serotonergic interneuron

    J Neurosci

    (2009)
  • B.R. Johnson et al.

    Dopamine modulation of phasing of activity in a rhythmic motor network: contribution of synaptic and intrinsic modulatory actions

    J Neurophysiol

    (2005)
  • V. Thirumalai et al.

    Red pigment concentrating hormone strongly enhances the strength of the feedback to the pyloric rhythm oscillator but has little effect on pyloric rhythm period

    J Neurophysiol

    (2006)
  • S. Zhao et al.

    Peptide neuromodulation of synaptic dynamics in an oscillatory network

    J Neurosci

    (2011)
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