Research in the Section on Nervous System Development and Plasticity, is concerned with understanding the molecular and cellular mechanisms by which functional activity in the brain regulates development of the nervous system during late stages of fetal development and early postnatal life. This work has three main areas of emphasis: 1. Determining how different patterns of neural impulses regulate specific genes controlling development and plasticity of the nervous system. This includes effects of impulse activity on neurons and glia and the molecular signaling pathways regulating gene expression in these cells in response to neural impulses. 2. Investigating how neurons and non-neuronal cells (glia) interact, communicate, and cooperate functionally. A major emphasis of this current research is in understanding how myelin (white matter in the brain) is involved in learning, cognition, child development, and psychiatric disorders. This research is exploring how glia sense neural impulse activity at synapses and non-synaptic regions, and the functional and developmental consequences of activity-dependent regulation of neurons and glia. 3. Determining the molecular mechanisms converting short-term memory into long-term memory, and in particular, how gene expression necessary for long-term memory is controlled. Cellular, molecular, and electrophysiological studies on synaptic plasticity (LTP) in hippocampal brain slice are used. Major achievements this year include showing that myelination is regulated by electrical activity in nerve fibers (axons);determining how neurotransmitter is released along axons firing action potentials;and that the strength of developing synapses is regulated by the level of impulse activity in developing neural circuits through the action of a newly described micro RNA, mir-485. Myelin, the multilayered membrane of insulation wrapped around nerve fibers by glial cells (oligodendrocytes), is essential for nervous system function, increasing conduction velocity by at least 50 times. Myelination is an essential part of brain development. The processes controlling myelination of appropriate axons is are not well understood. Myelination begins in late fetal life and continues through childhood, and adolescence, but myelination of some brain regions is not completed until the early twenties. Our research shows that release of the neurotransmitter glutamate from vesicles along axons promotes the initial events in myelin induction. This includes stimulating the formation of cholesterol-rich signaling domains between oligodendrocytes and axons, and increasing the local synthesis of the major protein in the myelin sheath, myelin basic protein, through Fyn kinase dependent signaling. This axon-oligodendrocyte signaling would promote myelination of electrically active axons to regulate neural development and function according to environmental experience. The findings are also relevant to demyelinating disorders, such as multiple sclerosis, and remyelination after axon injury. We also find that other signaling molecules released from axons, notably ATP, act to stimulate differentiation of oligodendrocytes with increases myelination. In collaboration with colleagues in Italy, found that a new membrane receptor on oligodendrocyte progenitor cells, GPR-17, regulates oligodendrocyte differentiation. The release of neuronal messengers outside synapses has broad biological implications, particularly with regard to communication between axons and glia. We have identified a mechanism for nonsynaptic, nonvesicular release of ATP from axons through volume-activated anion channels (VAACs) activated by microscopic axon swelling during action potential firing. These studies combined imaging single photons to measure ATP release, together with imaging intrinsic optical signals, intracellular calcium, time-lapse video, and confocal microscopy. Microscopic axon swelling accompanying electrical depolarization of axons activates VAACs to release ATP. This nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells in normal conditions, development, and disease. Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are coordinately regulated during homeostatic synaptic plasticity is unknown. Micro RNAs (miRNAs) exert regulatory control over mRNA stability and translation and they may contribute to local activity-dependent posttranscriptional control of synapse associated mRNAs. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of mRNAs that are rapidly destabilized after increasing impulse activity in hippocample neurons in culture, we identified a developmentally and activity-regulated miRNA (miR485) and found that it controls dendritic spine number and synapse formation in an activity dependent homeostatic manner. Many plasticity associated genes contain predicted miR-485 binding sites including the presynaptic protein SV2A. We found that miR-485 decreases SV2A abundance and negatively regulates dendritic spine density, postsynaptic density protein (PSD-95) clustering, and surface expression of GluR2. Over expression of miR485 reduces spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current analysis and FM 1-43 staining. These findings show that miRNAs participate in homeostatic synaptic plasticity with possible implications in neurological disorders such as Huntington and Alzheimer's disease, where miR-485 has been found to be dysregulated.

Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2011
Total Cost
$1,067,746
Indirect Cost
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Lee, Philip R; Cohen, Jonathan E; Iacobas, Dumitru A et al. (2017) Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons. Sci Rep 7:43765
Martin, Jasmin E; Nguyen, TrangKimberly T; Grunseich, Christopher et al. (2017) Decreased Motor Neuron Support by SMA Astrocytes due to Diminished MCP1 Secretion. J Neurosci 37:5309-5318
Fields, R Douglas; Dutta, Dipankar J; Belgrad, Jillian et al. (2017) Cholinergic signaling in myelination. Glia 65:687-698
Ravin, Rea; Blank, Paul S; Busse, Brad et al. (2016) Blast shockwaves propagate Ca(2+) activity via purinergic astrocyte networks in human central nervous system cells. Sci Rep 6:25713
Bukalo, Olena; Lee, Philip R; Fields, R Douglas (2016) BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus. Neurosci Lett 635:97-102
Pourshafie, Naemeh; Lee, Philip R; Chen, Ke-Lian et al. (2016) MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy. Mol Ther 24:937-45
Filley, Christopher M; Fields, R Douglas (2016) White Matter and Cognition: Making the Connection. J Neurophysiol :jn.00221.2016
Wake, Hiroaki; Ortiz, Fernando C; Woo, Dong Ho et al. (2015) Nonsynaptic junctions on myelinating glia promote preferential myelination of electrically active axons. Nat Commun 6:7844
Fields, R Douglas (2015) A new mechanism of nervous system plasticity: activity-dependent myelination. Nat Rev Neurosci 16:756-67
Nunez, Paul L; Srinivasan, Ramesh; Fields, R Douglas (2015) EEG functional connectivity, axon delays and white matter disease. Clin Neurophysiol 126:110-20

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