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Activity-dependent neurotransmitter respecification

Key Points

  • The transmitters expressed by neurons have been thought to be a constant and immutable aspect of neuronal identity, but recent work shows that electrical activity can respecify transmitter expression in both the developing and the mature nervous system.

  • This process seems to promote homeostatic equilibrium of excitability by changing the transmitters neurons synthesize and release, suggesting that this equilibrium is important for normal maturation of the nervous system and maintenance of homeostasis in circuits. Perturbations of embryonic activity with drugs may alter the composition and function of the nervous system by disturbing crucial homeostatic regulation of excitability.

  • Transmitter respecification involves induction of transmitter expression in reserve pool neurons that already express other transmitters and are wired into circuits. Activity reprograms these neurons to express an additional transmitter or switch from one transmitter to another.

  • At the molecular level, activity engages the expression of transcription factors that alter the expression of genes encoding enzymes involved in neurotransmitter synthesis and transmitter transporters that drive transmitter respecification.

  • Activity-dependent changes in transmitter specification are matched by corresponding changes in the expression of the cognate postsynaptic receptors, enabling synaptic transmission by the novel transmitters.

  • Neurons expressing a new neurotransmitter can drive appropriate behaviours at early stages of development, putting activity-dependent transmitter specification on a functional map. Given that the structure and function of the nervous system track changes in the environment, it seems likely that activity-dependent changes in transmitter identity are a mechanism that enables behaviour to change flexibly.

  • Pathological loss of neurotransmitters and their receptors may be treated therapeutically by sensorimotor stimulation that drives transmitter respecification and hijacks existing neuronal circuitry.

Abstract

For many years it has been assumed that the identity of the transmitters expressed by neurons is stable and unchanging. Recent work, however, shows that electrical activity can respecify neurotransmitter expression during development and in the mature nervous system, and an understanding is emerging of the molecular mechanisms underlying activity-dependent transmitter respecification. Changes in postsynaptic neurotransmitter receptor expression accompany and match changes in transmitter specification, thus enabling synaptic transmission. The functional roles of neurotransmitter respecification are beginning to be understood and appear to involve homeostatic synaptic regulation, which in turn influences behaviour. Activation of this novel form of plasticity by sensorimotor stimuli may provide clinical benefits.

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Figure 1: Developmental context for activity-dependent neurotransmitter respecification.
Figure 2: Activity-dependent transmitter respecification in neurons distinguished by molecular markers of neuronal identity in the developing Xenopus laevis spinal cord and hypothalamus.
Figure 3: Molecular mechanisms of activity-dependent transmitter respecification in the Xenopus laevis CNS.
Figure 4: Transmitter receptor expression matches activity-dependent transmitter respecification in Xenopus laevis larvae.
Figure 5: Activity-dependent changes in transmitter expression regulate behaviours in Xenopus laevis larvae.

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Acknowledgements

I thank L. Borodinsky, D. Dulcis and M. Demarque for their comments and suggestions for the manuscript. N.C.S. is supported by grants NS15918 and NS57690 from the US National Institutes of Health.

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Glossary

Activity-dependent neurotransmitter respecification

Expression or loss of a transmitter or switch between expression of one transmitter and another in response to changes in activity.

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Spitzer, N. Activity-dependent neurotransmitter respecification. Nat Rev Neurosci 13, 94–106 (2012). https://doi.org/10.1038/nrn3154

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