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The Journal of Neuroscience, May 1, 2002, 22(9):3543-3552

GAP-43 Is Critical for Normal Development of the Serotonergic Innervation in Forebrain

Stacy L. Donovan1, Laura A. Mamounas3, 4, Anne M. Andrews5, Mary E. Blue2, 3, 6, and James S. McCasland1

1 Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, New York 13210, 2 Departments of Neurology and 3 Neuroscience and 4 Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 5 Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, and 6 Kennedy Krieger Research Institute, Baltimore, Maryland 21205

Serotonergic (5-HT) axons from the raphe nuclei are among the earliest afferents to innervate the developing forebrain. The present study examined whether GAP-43, a growth-associated protein expressed on growing 5-HT axons, is necessary for normal 5-HT axonal outgrowth and terminal arborization during the perinatal period. We found a nearly complete failure of 5-HT immunoreactive axons to innervate the cortex and hippocampus in GAP-43-null (GAP43-/-) mice. Abnormal ingrowth of 5-HT axons was apparent on postnatal day 0 (P0); quantitative analysis of P7 brains revealed significant reductions in the density of 5-HT axons in the cortex and hippocampus of GAP43-/- mice relative to wild-type (WT) controls. In contrast, 5-HT axon density was normal in the striatum, septum, and amygdala and dramatically higher than normal in the thalamus of GAP43-/- mice. Concentrations of serotonin and its metabolite, 5-hydroxyindolacetic acid, and norepinephrine were decreased markedly in the anterior and posterior cerebrum but increased in the brainstem of GAP43-/- mice. Cell loss could not account for these abnormalities, because unbiased stereological analysis showed no significant difference in the number of 5-HT dorsal raphe neurons in P7 GAP43-/- versus WT mice. The aberrant 5-HT innervation pattern persisted at P21, indicating a long-term alteration of 5-HT projections to forebrain in the absence of GAP-43. In heterozygotes, the density and morphology of 5-HT axons was intermediate between WT and homozygous GAP43-/- mice. These results suggest that GAP-43 is a key regulator in normal pathfinding and arborization of 5-HT axons during early brain development.

Key words: serotonin; terminal arborization; neocortex; hippocampus; GAP-43; denervation; knock-out mice

Copyright © 2002 Society for Neuroscience  0270-6474/02/2293543-10$05.00/0


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