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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS015918-34A1
Application #
8753826
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
34
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Guemez-Gamboa, Alicia; Xu, Lin; Meng, Da et al. (2014) Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching. Neuron 82:1004-16
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Spitzer, Nicholas C (2012) Activity-dependent neurotransmitter respecification. Nat Rev Neurosci 13:94-106
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
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Xiao, Qian; Xu, Lin; Spitzer, Nicholas C (2010) Target-dependent regulation of neurotransmitter specification and embryonic neuronal calcium spike activity. J Neurosci 30:5792-801
Demarque, Michael; Spitzer, Nicholas C (2010) Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior. Neuron 67:321-34
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Root, Cory M; Velazquez-Ulloa, Norma A; Monsalve, Gabriela C et al. (2008) Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification. J Neurosci 28:4777-84
Dulcis, Davide; Spitzer, Nicholas C (2008) Illumination controls differentiation of dopamine neurons regulating behaviour. Nature 456:195-201

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