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Journal of Neuroscience, Vol 13, 3848-3863, Copyright © 1993 by Society for Neuroscience
Transplanted neocortical neurons migrate selectively into regions of neuronal degeneration produced by chromophore-targeted laser photolysis
JD Macklis
Department of Neurology, Harvard Medical School, Boston, Massachusetts.
Selective degeneration of neocortical callosal pyramidal neurons by
noninvasive laser illumination was used for directed studies of neocortical
transplantation, to test the hypothesis that transplanted embryonic neurons
may seek to restore normal cytoarchitecture within an appropriately
permissive local environment. At long wavelengths that penetrate through
tissue without major absorption, photolysis can cause extremely selective
degeneration to desired subpopulations of targeted neurons in vivo (Macklis
and Madison, 1991; Madison and Macklis, 1993). Cell death is geographically
defined and slowly progressive, allowing control over the anatomical
substrate for transplantation. Targeting occurs by retrograde incorporation
of cytolytic chromophores that are activated by specific-wavelength light.
Intermixed neurons, glia, axons, blood vessels, and connective tissue
remain intact. Degeneration was effected within neocortical lamina II/III
of neonatal mouse pups following targeting in utero or early postnatally
with photoactive nanospheres. Total neuron density was reduced typically by
25-30% within defined areas, with approximately 60% loss of large
projection neurons and no change in the number of small, presumptive
interneurons. Embryonic day 17 neocortical cell suspensions, which included
recently postmitotic neurons destined to form lamina II/III, were
transplanted lateral to these regions of ongoing neuron degeneration in
juvenile mice. Cellular injections spanned laminae II-V, to provide donor
neurons with both lateral and laminar choice for possible migration and
integration. Donor cells were labeled in vitro with unique fluorescent and
electron-dense nanospheres that allowed distinct identification of donor
cells at both light and electron microscopic levels. Control experiments
included neocortical transplants into intact age-matched hosts, into hosts
with kainic acid lesions to neocortex, or distant to the region of
photolytic neuronal degeneration; embryonic cerebellar transplants to the
regions of selective photolytic degeneration; and grafts of hypoosmotically
lysed neocortical cells to lesioned regions. After survival times of 1 hr
to 12 weeks, labeled neurons were identified morphologically and positions
were digitized for qualitative and quantitative analysis of position and
specificity of migration and cellular integration; electron microscopy was
used to confirm further the donor identities of migrated neurons. Neurons
placed near host zones of photolytic neuron degeneration migrated up to 780
microns specifically within these zones; approximately 44% of donor neurons
migrated significantly beyond the injection site to enter these regions.
Migration and integration did not occur in normal, unaffected deeper layers
IV-VI of these experimental mice, or in the normal lamina II/III bordering
the transplantation site on the side opposite the neuron-deficient region.
Control grafts of all five types revealed only minimal local spread without
laminar preference.(ABSTRACT TRUNCATED AT 400 WORDS)
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