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Nervous System Development and Plasticity

R. Douglas Fields, PhD, Head, Section on Nervous System Development and Plasticity
Philip Lee, PhD, Staff Scientist
Olena Bukalo, PhD, Visiting Fellow
Hae Ung Lee, PhD, Visiting Fellow
Hiroaki Wake, MD, PhD, Visiting Fellow
Jerome Staal, PhD, Special Volunteer
Michelle Klippel, BS, Technician Biologist

Healthy brain and cognitive development in children is central to the mission of NICHD. Unlike many other organs and the brains of most animals, the human brain continues to develop postnatally, through adolescence, and into early adulthood. The prolonged postnatal period of brain development allows environmental experiences to influence brain structure and function, rather than having brain function specified entirely by genes. Activity-dependent plasticity also compensates for developmental defects and brain injury. 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. We are especially interested in exploring new mechanisms of activity-dependent nervous system plasticity that are particularly relevant to the period of childhood. The work has three main areas of emphasis.

Myelination and neuron-glia interactions: Traditionally, the field of activity-dependent nervous system development has focused on synapses, and we continue to explore synaptic plasticity. However, our research is advancing understanding of how non-neuronal brain cells (glia) sense neural impulse activity at both synaptic and non-synaptic regions and is determining the developmental consequences of such sensing. A major emphasis of this current research is to understand how myelin (white matter in the brain) is regulated by functional activity. Our studies have identified several cellular and molecular mechanisms for activity-dependent myelination, and the findings have important implications for normal brain development, learning and cognition, and psychiatric disorders.

Cellular mechanisms of learning: Learning is perhaps the most important function of childhood. Our research is identifying the molecular mechanisms converting short-term memory into long-term memory. In particular, we are investigating how gene expression necessary for long-term memory is controlled and how intrinsic activity in the brain (oscillations and neuronal firing) works together with sensory-evoked stimulation to form memories.

Gene regulation by neuronal firing: Information in the nervous system is encoded in the temporal pattern of action potential firing. If functional experiences produce lasting effects on brain development and plasticity, then specific genes must be regulated by specific patterns of impulse firing. We have verified this hypothesis and are determining how different patterns of neural impulses regulate specific genes controlling development and plasticity of the nervous system and how impulse activity affects neurons and glia, and we are identifying the molecular signaling networks regulating gene expression in response to neural impulses.

Regulation of myelination by neural impulse activity

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Figure 1. Myelin

Myelin, the multilayered membrane of insulation wrapped around nerve fibers (axons) by glial cells (oligodendrocytes), is essential for nervous system function, increasing conduction velocity at least 50-fold. Myelination is an essential part of brain development. The processes controlling myelination of appropriate axons 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 neurotransmitters are released along axons firing action potentials. The neurotransmitters activate receptors on myelinating glia (Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system) as well as astrocytes and other cells that in turn release growth factors or cytokines that regulate development of myelinating glia.

In addition to establishing the effects of impulse activity on proliferation and development of myelinating glia, we determined that release of the neurotransmitter glutamate from vesicles along axons promotes the initial events in myelin induction, including 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. Axon-oligodendrocyte signaling would thus 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 found that other signaling molecules released from axons, notably ATP, stimulate differentiation of oligodendrocytes with increases myelination. In collaboration with colleagues in Italy, we 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 identified a mechanism for nonsynaptic, nonvesicular release of ATP from axons through volume-activated anion channels (VAACs), whch are activated by microscopic axon swelling during action potential firing. The studies combine imaging of single photons to measure ATP release in a luciferin/luciferase assay with imaging of intrinsic optical signals, intracellular calcium, time-lapse video, and confocal microscopy. Microscopic axon swelling accompanying electrical depolarization of axons activates the VAACs to release ATP. Such nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells under normal conditions, during development, and in disease.

Synaptic plasticity

To maintain the general level of neural impulse activity within normal limits, homeostatic mechanisms are required to control the formation and maintenance of synaptic connections during development and learning. How genes controlling these processes are coordinately regulated during homeostatic synaptic plasticity is unknown. Micro RNAs (miRNAs) exert regulatory control over mRNA stability and protein translation and may contribute to local activity-dependent post-transcriptional control of synapse-associated mRNAs. Using a bioinformatics screen to search for sequence motifs enriched in the 3′ UTR of mRNAs that are rapidly destabilized after increasing impulse activity in hippocampal neurons, we identified a developmentally and activity-regulated miRNA (miR485) and showed 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 for the presynaptic protein SV2A. We found that miR-485 reduces SV2A abundance and negatively regulates dendritic spine density, postsynaptic density protein (PSD-95) clustering, and surface expression of the glutamate receptor GluR2. Overexpression of miR485 reduces spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current analysis and FM 1-43 staining. The findings show that miRNAs participate in homeostatic synaptic plasticity, with possible implications for neurological disorders such as Huntington and Alzheimer's disease, where miR-485 has been found to be dysregulated.

Hippocampal synaptic plasticity

It is widely appreciated that there are two types of memory: short-term and long-term. It has been known for decades that gene expression is necessary to convert short-term into long-term memory, but it is not known how signals reach the nucleus to initiate this process or which genes make memories permanent. Long-term potentiation (LTP) and long-term depression (LTD) are two widely studied forms of synaptic plasticity that can be recorded electrophysiologically in the hippocampus, and these phenomena are believed to represent a cellular basis for memory. We use cDNA microarrays to investigate the signaling pathways, genes, and proteins involved in LTP and LTD. This work is contributing to a better understand of how regulatory networks are controlled by the appropriate patterns of impulses, leading to different forms of synaptic plasticity, and identifying new molecular mechanisms regulating synaptic strength.

In contrast to sensory-evoked stimulation, intrinsic activity in the brain often operates in non-traditional modes. We have identified how non-traditional modes of neuronal firing in the hippocampus during high-frequency oscillations (sharp-wave ripple complexes) affect synaptic plasticity in the process of memory consolidation during slow wave sleep.

Regulation of gene expression by action-potential firing patterns

To determine how gene expression in neurons and glia is regulated by impulse firing, we stimulate nerve cells to fire impulses in differing patterns by delivering electrical stimulation through platinum electrodes in specially designed cell culture dishes. After stimulation, we measured mRNA and protein expression by gene arrays, quantitative RT-PCR (reverse transcriptase–polymerase chain reaction), Western blot, and immunocytochemistry. The results confirm our hypothesis that precise patterns of impulse activity can increase or decrease expression of specific genes (in neurons and glia). The experiments are revealing signaling and gene-regulatory networks that respond selectively to appropriate temporal patterns of action potential firing. Temporal aspects of intracellular calcium signaling are particularly important in regulating gene expression according to neural impulse firing patterns in normal and pathological conditions. Our findings thus provide a deeper understanding of how nervous system development and plasticity is regulated by information coded in the temporal pattern of impulse firing in the brain and have relevance to chronic pain and the regulation of nervous system development and myelination by functional activity.

Additional Funding

Japanese Society for the Promotion of Science in support of Dr. Wake
NSF grant SMA-1258562, awarded Sept. 19, 2012, to Dr. Fields as Co-PI with Dr. Beth Stevens, Harvard Medical School
DOD Grant: 2012, Gulf War Illness Research Program Consortium Award, CDMRP Number: GW120037, Project Duration: 48 months

Publications

Wake H, Lee PR, Fields RD. Control of local protein synthesis and initial events in myelination by action potentials. Science 2011;333:1647-1651.
Cohen JE, Lee PR, Chen S, Li W, Fields RD. MicroRNA regulation of homeostatic synaptic plasticity. Proc Natl Acad Sci USA 2011;108:11650-11655.
Fields RD. Nonsynaptic and nonvesicular ATP release from neurons and relevance to neuron-glia signaling. Semin Cell Dev Biol 2011;22:214-219.
Fields RD. Signaling by neuronal swelling. Sci Signal 2011;4(155):tr1.
Zatorre RJ, Fields RD, Johansen-Berg H. Plasticity in gray and white: neuroimaging changes in brain structure during learing. Nat Neurosci 2012;15:528-536.

Contact

For more information, email fieldsd@mail.nih.gov or visit nsdps.nichd.nih.gov

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