GAP-43 is critical for normal development of the serotonergic innervation in forebrain.
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.
Donovan
Stacy L
SL
Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
Mamounas
Laura A
LA
Andrews
Anne M
AM
Blue
Mary E
ME
McCasland
James S
JS
D000375:Aging / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D001933:Brain Stem / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002452:Cell Count; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D019922:GAP-43 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D006720:Homozygote; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D011903:Raphe Nuclei / Q000166:cytology / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013687:Telencephalon / Q000378:metabolism; D013788:Thalamus / Q000166:cytology / Q000378:metabolism
D002352:Carrier Proteins; D019922:GAP-43 Protein; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D009638:Norepinephrine