Our perceptions, behaviors, emotions, memories and intelligence depend on the appropriate synthesis and release of specific neurotransmitters in the brain. Since the award of the Nobel Prize for the discovery of chemical synaptic transmission, it has been thought that transmitters are fixed and invariant throughout life and that the plasticity of the nervous system consists of changes in the strength and number of synapses. We have discovered that activity plays a key role in transmitter specification in the developing spinal cor, regulating the specification of glutamate, an excitatory transmitter, versus GABA, an inhibitory transmitter. This discovery contrasts sharply with the current general view of transmitter constancy and identifies another way that the nervous system can adapt to the environment. Strikingly, we have discovered that transmitter switching also takes place in the adult mammalian brain. These findings lead to several related questions: 1) Is activity-dependent transmitter respecification cell-autonomous in the embryonic Xenopus spinal cord? Do patterns of calcium spike activity regulate transmitter identity in the neurons generating them or does regulation depend on the activity of neighboring cells? 2) Does activity-dependent transmitter respecification involve the action of secreted factors? If so, what are they? 3) What is the molecular signaling cascade that drives transmitter respecification? How is calcium spike activity linked to transmitter switching? The immediate goals of this research are to test specific hypotheses about the mechanisms by which natural, spontaneous electrical activity regulates transmitter specification in the vertebrate CNS. We expect to provide information about the cellular and molecular machinery that governs transmitter specification during development. The long term goals are to use this understanding of the molecular pathways of activity-dependent transmitter respecification to develop new tools useful for treating disorders of the nervous system.

Public Health Relevance

Appropriate expression of neurotransmitters and their receptors is essential for the normal function of the nervous system. We have discovered that electrical activity plays a key role in transmitter specification in the developing spinal cord, regulating the specification of glutamate, an excitatory transmitter, versus GABA, an inhibitory transmitter. Here we propose to determine the molecular mechanism regulating this process.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Morris, Jill A
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University of California San Diego
Schools of Arts and Sciences
La Jolla
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Dulcis, Davide; Lippi, Giordano; Stark, Christiana J et al. (2017) Neurotransmitter Switching Regulated by miRNAs Controls Changes in Social Preference. Neuron 95:1319-1333.e5
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Guemez-Gamboa, Alicia; Xu, Lin; Meng, Da et al. (2014) Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching. Neuron 82:1004-16
Spitzer, Nicholas C; Borodinsky, Laura N; Root, Cory M (2013) Imaging and manipulating calcium transients in developing Xenopus spinal neurons. Cold Spring Harb Protoc 2013:653-64
Spitzer, Nicholas C (2012) Activity-dependent neurotransmitter respecification. Nat Rev Neurosci 13:94-106
Demarque, Michael; Spitzer, Nicholas C (2012) Neurotransmitter phenotype plasticity: an unexpected mechanism in the toolbox of network activity homeostasis. Dev Neurobiol 72:22-32
Dulcis, Davide; Spitzer, Nicholas C (2012) Reserve pool neuron transmitter respecification: Novel neuroplasticity. Dev Neurobiol 72:465-74
Rosenberg, Sheila S; Spitzer, Nicholas C (2011) Calcium signaling in neuronal development. Cold Spring Harb Perspect Biol 3:a004259
Nicol, Xavier; Hong, Kwan Pyo; Spitzer, Nicholas C (2011) Spatial and temporal second messenger codes for growth cone turning. Proc Natl Acad Sci U S A 108:13776-81
Velazquez-Ulloa, Norma A; Spitzer, Nicholas C; Dulcis, Davide (2011) Contexts for dopamine specification by calcium spike activity in the CNS. J Neurosci 31:78-88

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