The contributions of genetic and environmental factors to the phenotypes of an organism are a perennial subject of the nature and nurture debate. It is now generally accepted that environmental factors are important in the determination of phenotypes by the genotypes, or nature through nurture. One of the best entry points to exploring the complex network of gene-environment interactions is through studies of neuronal and behavioral plasticity. Nervous systems are endowed with the capacity of self-modification in response to experience and external stimuli. Upon stress or injury by environmental challenges or system perturbations, neuro-protective and homeostatic mechanisms are evoked by intrinsic plasticity in neuronal and network functional organization.
The specific aims of this proposal are: 1) To investigate extrinsic factors, including elevated environmental temperature and social deprivation, that influence neuronal growth and excitability as revealed by the striking phenotypes of Hk and Sh mutations affecting different K+ channel subunits. The cellular mechanisms in response to these stressors during development will be analyzed to demonstrate the underlying common features of the diverse forms of neural plasticity. 2) To study the intrinsic developmental regulation mechanisms that enable neuronal adjustment for recovering function upon mutational perturbations of ion channel function and membrane excitability. Striking plasticity in restoring synaptic stability is revealed by slo and Sh mutations, which provide opportunities to identify interacting genes in signal transduction pathways in the associated homeostatic processes. The results will provide unique opportunities to test three major hypotheses for the common threads linking different forms of neuronal plasticity: 1) Membrane excitability mechanism is a major player in neuronal homeostatic regulation in response to environmental stresses or genetic perturbations. 2) Metabolic stress as reflected by ROS accumulation triggers modifications of neuronal excitability and neural circuit function. 3) Activity-dependent Ca accumulation activates Ca/CaM-dependent adenylyl cyclase (encoded by rut) that plays a pivotal role in initiating different cascade events for modulation or synthesis of downstream effectors, such as ion channels, in homeostatic modifications.

Public Health Relevance

The purpose of this study is to unravel the common threads linking different forms of neuronal and behavioral plasticity. We focus on mechanisms of homeostatic regulation of neuronal excitability and synaptic efficacy that enable adjustment and restoration of nervous system function upon environmental or mutational perturbations. The findings will have direct implications in the influence of environmental stress, social deprivation, and behavioral conditioning on mental and physical health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088804-21
Application #
8280408
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Sesma, Michael A
Project Start
1988-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
21
Fiscal Year
2012
Total Cost
$294,373
Indirect Cost
$96,393
Name
University of Iowa
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Ehaideb, Salleh N; Wignall, Elizabeth A; Kasuya, Junko et al. (2016) Mutation of orthologous prickle genes causes a similar epilepsy syndrome in flies and humans. Ann Clin Transl Neurol 3:695-707
Ueda, Atsushi; Wu, Chun-Fang (2015) The role of cAMP in synaptic homeostasis in response to environmental temperature challenges and hyperexcitability mutations. Front Cell Neurosci 9:10
Liu, Lijuan; Wu, Chun-Fang (2014) Distinct effects of Abelson kinase mutations on myocytes and neurons in dissociated Drosophila embryonic cultures: mimicking of high temperature. PLoS One 9:e86438
Ehaideb, Salleh N; Iyengar, Atulya; Ueda, Atsushi et al. (2014) prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies. Proc Natl Acad Sci U S A 111:11187-92
Iyengar, Atulya; Wu, Chun-Fang (2014) Flight and seizure motor patterns in Drosophila mutants: simultaneous acoustic and electrophysiological recordings of wing beats and flight muscle activity. J Neurogenet 28:316-28
Lee, Jihye; Ueda, Atsushi; Wu, Chun-Fang (2014) Distinct roles of Drosophila cacophony and Dmca1D Ca(2+) channels in synaptic homeostasis: genetic interactions with slowpoke Ca(2+) -activated BK channels in presynaptic excitability and postsynaptic response. Dev Neurobiol 74:1-15
Wise, Alexandria; Schatoff, Emma; Flores, Julian et al. (2013) Drosophila-Cdh1 (Rap/Fzr) a regulatory subunit of APC/C is required for synaptic morphology, synaptic transmission and locomotion. Int J Dev Neurosci 31:624-33
Ueda, Atsushi; Wu, Chun-Fang (2012) Cyclic adenosine monophosphate metabolism in synaptic growth, strength, and precision: neural and behavioral phenotype-specific counterbalancing effects between dnc phosphodiesterase and rut adenylyl cyclase mutations. J Neurogenet 26:64-81
Iyengar, Atulya; Imoehl, Jordan; Ueda, Atsushi et al. (2012) Automated quantification of locomotion, social interaction, and mate preference in Drosophila mutants. J Neurogenet 26:306-16
Burg, Martin G; Wu, Chun-Fang (2012) Mechanical and temperature stressor-induced seizure-and-paralysis behaviors in Drosophila bang-sensitive mutants. J Neurogenet 26:189-97

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