Research Highlights

NCMIR collaborators reveal how new neurons, born in the hippocampus, wire into the brain’s circuitry

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3-D reconstruction of a filopodia (green) extending from a dendrite (visualized using electron tomography) and apposed to a pre-existing synapse (blue & red). Image courtesy of Nicolas Toni and Fred Gage of the Salk Institute of Biological Sciences).

May 2007

Just over a decade ago the idea that the mammalian brain contains stem cells that divide and differentiate into new neurons continually throughout life was largely unimaginable. However, with the recent body of research showing that areas of the adult brain continually undergo neurogenesis, neuroscientists have adopted a new paradigm in thinking about the brain. To explore how newborn neurons wire into the brain’s environs, Nicolas Toni, Fred Gage, and their Salk Institute of Biological Studies colleagues collaborated with NCMIR researchers to reveal a detailed picture of the cellular mechanisms active during neurogenesis in adult mice. Last week, they reported their findings in the online edition of Nature Neuroscience.

Central to the brain's intricately designed neural wiring system is the synapse. Synapses, the minute junctions where nerve impulses are transmitted from one neuron to another, are the main circuits of information flow and storage in the brain. Learning and memory is thought to be centered on the synapse. So, elucidating the mechanisms that permit neurons to establish new connections with neighboring neurons has become a subject of much interest throughout the neuroscience community. And challenging too, since the thousands of minute synapses that comprise each neuron-neuron interaction are too small to be adequately resolved with light microscopy and yet too large to be characterized within single thin sections for electron microscopy.

Using live-imaging confocal microscopy and NCMIR’s expertise in intracellular injection and 3D electron tomography, the research team was able to characterize the morphological changes of the newborn neurons and their interaction with pre-existing neurons over the course of a half year. To do this, they injected a virus carrying a gene for a green fluorescent protein into the neural stem cells and documented the lives of the fluorescing newborn as they attempted to integrate themselves into the brain’s neural circuitry. Using electron tomography and serial section electron microcopy to further visualize changes taking place at the scale of nanometers, the researchers revealed that the newborn’s motile filopodia processes (future spines) preferentially seek out active presynaptic axons. “When we analyzed them in three dimensions, the tip of the filopodia was preferentially associated with synapses already connected to other neurons,” says postdoc fellow Nicolas Toni, who directed the present study.

However, as the new neurons matured, the tiny tips filled out and started to monopolize the synaptic connections. This supports the view that new neurons integrate at very specific points in the network, at which they may replace pre-existing connections.

Understanding how newborn neurons integrate into mature brains has implications for developing new methods of replacing brain tissue damaged from trauma or neurodegenerative diseases such as Parkinson’s or Alzheimer’s disease. The present study complements NCMIR’s decade-long progress in establishing optimal methods for visualizing and measuring these important structures using high-resolution light microscopy combined with electron tomography (Martone et. al. 1996, 2000; Capani et. al. 2001; Bushong et al 2004; Coogan et al 2005) while also driving the development of new imaging techniques for researchers examining other biological structures dwelling at the scale between nanometers and tens of microns, the mesoscale.

Additional information and images are found in the Salk Institute’s May 7, 2007 press release. Tomographic data collected in this study will be publicly available through NCMIR’s Cell Centered Database.

Citation:

Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, van Praag H, Martone ME, Ellisman MH and Gage FH (2007) Synapse formation on neurons born in the adult hippocampus. Nature Neuroscience Online publication: May 7 2007.

Literature cited:

Bushong EA, Martone ME, and Ellisman MH (2004) Maturation of Astrocyte Morphology and the Establishment of Astrocyte Domains During Postnatal Hippocampal Development. Intl J Developmental Neurosci, 22(2): 73-86.

Capani F, Martone ME, Deerinck TJ and Ellisman MH (2001) Selective localization of high concentrations of F-actin in subpopulations of dendritic spines in rat central nervous system: a three-dimensional electron microscopic study. J Comp Neurol 435(2):156-170.

Coggan JS, Bartol TM, Esquenazi E, Stiles JR, Lamont S, Martone ME, Berg DK, Ellisman MH, and Sejnowski TJ (2005) Evidence for ectopic neurotransmission at a neuronal synapse, Science, 2005 July 15;309(5733):446-51.

Martone ME, Pollock JA, Jones YZ and Ellisman MH (1996) Ultrastructural localization of dendritic messenger RNA in adult rat hippocampus. J Neurosci 16(23):7437-7446.

Martone ME, Hu BR and Ellisman MH (2000) Alterations of hippocampal postsynaptic densities following transient ischemia. Hippocampus 10(5):610-616.