Our previous work discovered developmental changes in expression of voltage-dependent and ligand-activated channels during early differentiation of amphibian spinal neurons. These findings raised the possibility that early forms of ion channel activity participate in signal transduction that influences subsequent steps of development. In recent studies we have discovered that spontaneous calcium spikes regulate expression of neurotransmitters in neurons of the spinal cord, identified ligands that drive this spontaneous activity, and shown that neurons with a modified transmitter phenotype select cognate receptors and form functional synapses. These findings lead to several related questions: 1) How general is activity-dependent transmitter specification, i.e. does calcium spike activity also regulate transmitter expression in the brain, and if so what are the underlying mechanisms? 2) Do natural environmental stimuli such as ambient light or temperature also influence transmitter specification, i.e. does the global environment in which differentiation occurs modulate this developmental process? The experimental perturbations previously exploited are not ones encountered during normal development and leave open the question of whether natural environmental stimuli influence the choice of transmitter for different classes of neurons. 3) Are there local environmental factors that interact with spike activity and contribute to transmitter specification? Our proposed research has four specific aims that analyze activity-dependent expression of biogenic amines (dopamine and serotonin) in the brain (aims 1 &2), address the function of natural environmental stimuli in specification of transmitter expression (aims 1-3), and analyze several regulatory mechanisms (aims 2 &4). The 2nd aim analyzes the role of activity-dependent transcription factors in regulating transmitter expression and the 4th aim investigates the interaction between early electrical activity and target-derived factors in transmitter specification. The immediate goal of this research is to test hypotheses about the role of electrical activity and natural environmental stimuli in transmitter specification in the vertebrate CNS. The long term goal is to provide information about the cellular and molecular machinery that governs neurotransmitter specification during development. It is expected that this work will contribute to understanding developmental disorders of the nervous system in which neurotransmitter expression is altered during embryonic and post-embryonic development.

Public Health Relevance

Cognitive disorders such as depression, schizophrenia and Parkinson's disease are disorders of neurotransmitter and neurotransmitter receptor metabolism. This research will provide information about the role of electrical activity and natural environmental stimuli in transmitter specification in the vertebrate nervous system. It is expected that this work will contribute to understanding developmental disorders of the nervous system in which neurotransmitter expression is altered during embryonic and post-embryonic development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS015918-33
Application #
8289543
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Morris, Jill A
Project Start
1980-01-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
33
Fiscal Year
2012
Total Cost
$331,209
Indirect Cost
$116,834
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
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
Demarque, Michael; Spitzer, Nicholas C (2012) Neurotransmitter phenotype plasticity: an unexpected mechanism in the toolbox of network activity homeostasis. Dev Neurobiol 72:22-32
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
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
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
Ben-Ari, Yehezkel; Spitzer, Nicholas C (2010) Phenotypic checkpoints regulate neuronal development. Trends Neurosci 33:485-92
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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