α-Ca2+/calmodulin-dependent protein kinase II contributes to the developmental programming of anxiety in serotonin receptor 1A knock-out mice

Luisa Lo Iacono, Cornelius Gross

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Mice lacking the serotonin receptor 1A [Htr1a knock-out (Htr1a KO)] display increased innate and conditioned anxiety-related behavior. Expression of the receptor in the mouse forebrain during development is sufficient to restore normal anxiety-related behavior to knock-out mice, demonstrating a role for serotonin in the developmental programming of anxiety circuits. However, the precise developmental period as well as the signaling pathways and neural substrates involved in this phenomenon are unknown. Here, we show that pharmacological blockade of the receptor from postnatal day 13 (P13)-P34 is sufficient to reproduce the knock-out phenotype in adulthood, thus defining a role for serotonin in the maturation and refinement of anxiety circuits during a limited postnatal period. Furthermore, we identify increases in the phosphorylation of α-Ca2+/calmodulin-dependent protein kinase II (αCaMKII) at threonine 286 in the hippocampus of young Htr1aKO mice under anxiety-provoking conditions. Increases in αCaMKII phosphorylation were most pronounced in the CA1 region of the hippocampus and were localized to the extrasynaptic compartment, consistent with a tissue-specific effect of the receptor. No changes in αCaMKII phosphorylation were found in adult knock-out mice, suggesting a transient role of αCaMKII as a downstream target of the receptor. Finally, the anxiety phenotype was abolished when knock-out mice were crossed to mice in which αCaMKII phosphorylation was compromised by the heterozygous mutation of threonine 286 into alanine. These findings suggest that modulation of αCaMKII function by serotonin during a restricted postnatal period contributes to the developmental programming of anxiety-related behavior.

Original languageEnglish
Pages (from-to)6250-6257
Number of pages8
JournalJournal of Neuroscience
Volume28
Issue number24
DOIs
Publication statusPublished - Jun 11 2008

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Receptor, Serotonin, 5-HT1A
Knockout Mice
Anxiety
Phosphorylation
Serotonin
Threonine
Hippocampus
Phenotype
Neural Pathways
Prosencephalon
Alanine
Pharmacology
Mutation

Keywords

  • 5-HT1A receptor
  • Anxiety
  • Autophosphorylation
  • CaMKII
  • CaMKII T286A
  • Postnatal development

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

α-Ca2+/calmodulin-dependent protein kinase II contributes to the developmental programming of anxiety in serotonin receptor 1A knock-out mice. / Iacono, Luisa Lo; Gross, Cornelius.

In: Journal of Neuroscience, Vol. 28, No. 24, 11.06.2008, p. 6250-6257.

Research output: Contribution to journalArticle

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