Visual system neurons are highly dependent on oxidative metabolism for their normal functioning. When energy supply is diminished, visual neurons are impacted first and more severely than other neurons. Defective energy metabolism often leads to severe visual deficits, even blindness. Energy metabolism can be studied indirectly by monitoring increased blood flow and glucose utilization to areas of increased visual activity. Our laboratory studies it directly by analyzing the molecular mechanism of its regulation in visual cortical neurons. In the current grant period, we discovered that neuronal activity and energy metabolism are tightly coupled even at the transcriptional level. The same transcription factor, nuclear respiratory factor 1 (NRF-1), co-regulate genes for energy generation (exemplified by cytochrome c oxidase [COX], without which oxidative metabolism cannot be completed and mitochondrial ATP cannot be generated) and genes for glutamatergic transmission (NMDA receptor subunits 1 and 2B [Grin1 and Grin 2b], AMPA receptor subunit 2 [Gria2], and neuronal nitric oxide synthase [Nos1], a downstream mediator of NMDA receptor action) in visual cortical neurons. To probe the mechanism further, the present proposal has 3 specific aims to test our 3 hypotheses: (1) NRF-1 does not act alone, but rather in conjunction with another transcription factor, nuclear respiratory factor 2 (NRF-2), to co-regulate energy metabolism and neurochemicals of excitatory transmission in visual cortical neurons. We propose 3 models of operation: a) NRF-2 does not regulate any glutamatergic neurochemicals;b) NRF-2 regulates the same neurochemicals as NRF-1, providing a redundant mechanism;and c) NRF-2 regulates glutamatergic neurochemicals complementary to those of NRF-1, effecting a complementary mechanism. A combination of models 2 and 3 is also possible.
This aim will be tested with multiple molecular biological approaches. (2) Even though NRF-1 and NRF-2 both regulate all COX subunit genes, they do not interact at the protein level. This parallel mechanism enables independent regulation by the two transcription factors.
This aim and hypothesis will be tested with co-immunoprecipitation and mammalian two-hybrid system. (3) A tripartite mechanism exists by which the same transcription factor, NRF-1, regulates genes for energy generation (COX), energy consumption (Na+K+ATPase), and glutamatergic neurochemicals that mediate excitatory synaptic communication. Documentation of NRF-1's role in regulating Na+K+ATPase will provide the missing link and complete the circle of coupling between energy metabolism and neuronal activity.
This aim and hypothesis will be tested with multiple molecular biological approaches as in aim 1. Results from these studies will significantly advance our understanding of the molecular mechanism by which energy generated exquisitely matches energy consumed by neuronal activity in visual cortical neuron. They will also provide the basis for future gene therapy for visual deficits resulting from faulty energy metabolism.

Public Health Relevance

The visual system ranks amongst the highest energy-consuming systems in the brain, and defective energy production can be detrimental to visual functioning, leading even to blindness. This project seeks to elucidate the basic mechanisms by which the regulation of energy generation, neuronal communication, and energy consumption are coordinately orchestrated at the molecular level by the same factor or factors in visual cortical neurons.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Steinmetz, Michael A
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Medical College of Wisconsin
Anatomy/Cell Biology
Schools of Medicine
United States
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Priya, Anusha; Johar, Kaid; Nair, Bindu et al. (2014) Nuclear respiratory factor 2 regulates the transcription of AMPA receptor subunit GluA2 (Gria2). Biochim Biophys Acta 1843:3018-28
Johar, Kaid; Priya, Anusha; Wong-Riley, Margaret T T (2014) Regulation of Na(+)/K(+)-ATPase by neuron-specific transcription factor Sp4: implication in the tight coupling of energy production, neuronal activity and energy consumption in neurons. Eur J Neurosci 39:566-78
Priya, Anusha; Johar, Kaid; Nair, Bindu et al. (2014) Specificity protein 4 (Sp4) regulates the transcription of AMPA receptor subunit GluA2 (Gria2). Biochim Biophys Acta 1843:1196-206
Johar, Kaid; Priya, Anusha; Dhar, Shilpa et al. (2013) Neuron-specific specificity protein 4 bigenomically regulates the transcription of all mitochondria- and nucleus-encoded cytochrome c oxidase subunit genes in neurons. J Neurochem 127:496-508
Priya, Anusha; Johar, Kaid; Wong-Riley, Margaret T T (2013) Nuclear respiratory factor 2 regulates the expression of the same NMDA receptor subunit genes as NRF-1: both factors act by a concurrent and parallel mechanism to couple energy metabolism and synaptic transmission. Biochim Biophys Acta 1833:48-58
Priya, Anusha; Johar, Kaid; Wong-Riley, Margaret T T (2013) Specificity protein 4 functionally regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B. Biochim Biophys Acta 1833:2745-56
Dhar, Shilpa S; Johar, Kaid; Wong-Riley, Margaret T T (2013) Bigenomic transcriptional regulation of all thirteen cytochrome c oxidase subunit genes by specificity protein 1. Open Biol 3:120176
Dhar, Shilpa S; Wong-Riley, Margaret T T (2011) The kinesin superfamily protein KIF17 is regulated by the same transcription factor (NRF-1) as its cargo NR2B in neurons. Biochim Biophys Acta 1813:403-11
Dhar, Shilpa S; Wong-Riley, Margaret T T (2010) Chromosome conformation capture of transcriptional interactions between cytochrome c oxidase genes and genes of glutamatergic synaptic transmission in neurons. J Neurochem 115:676-83
Liang, Huan Ling; Dhar, Shilpa S; Wong-Riley, Margaret T T (2010) p38 mitogen-activated protein kinase and calcium channels mediate signaling in depolarization-induced activation of peroxisome proliferator-activated receptor gamma coactivator-1alpha in neurons. J Neurosci Res 88:640-9

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