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

Stacy L. Donovan, Laura A. Mamounas, Anne M. Andrews, Mary E Blue, James S. McCasland

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3543-3552
Number of pages10
JournalJournal of Neuroscience
Volume22
Issue number9
StatePublished - May 1 2002

Fingerprint

GAP-43 Protein
Prosencephalon
Serotonin
Axons
Hippocampus
Raphe Nuclei
Brain
Cerebrum
Heterozygote
Amygdala
Thalamus
Brain Stem

Keywords

  • Denervation
  • GAP-43
  • Hippocampus
  • Knock-out mice
  • Neocortex
  • Serotonin
  • Terminal arborization

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Donovan, S. L., Mamounas, L. A., Andrews, A. M., Blue, M. E., & McCasland, J. S. (2002). GAP-43 Is Critical for Normal Development of the Serotonergic Innervation in Forebrain. Journal of Neuroscience, 22(9), 3543-3552.

GAP-43 Is Critical for Normal Development of the Serotonergic Innervation in Forebrain. / Donovan, Stacy L.; Mamounas, Laura A.; Andrews, Anne M.; Blue, Mary E; McCasland, James S.

In: Journal of Neuroscience, Vol. 22, No. 9, 01.05.2002, p. 3543-3552.

Research output: Contribution to journalArticle

Donovan, SL, Mamounas, LA, Andrews, AM, Blue, ME & McCasland, JS 2002, 'GAP-43 Is Critical for Normal Development of the Serotonergic Innervation in Forebrain', Journal of Neuroscience, vol. 22, no. 9, pp. 3543-3552.
Donovan SL, Mamounas LA, Andrews AM, Blue ME, McCasland JS. GAP-43 Is Critical for Normal Development of the Serotonergic Innervation in Forebrain. Journal of Neuroscience. 2002 May 1;22(9):3543-3552.
Donovan, Stacy L. ; Mamounas, Laura A. ; Andrews, Anne M. ; Blue, Mary E ; McCasland, James S. / GAP-43 Is Critical for Normal Development of the Serotonergic Innervation in Forebrain. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 9. pp. 3543-3552.
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AB - 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.

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