Alpha-Ca2+/calmodulin-dependent protein kinase II contributes to the developmental programming of anxiety in serotonin receptor 1A knock-out mice.
Mice lacking the serotonin receptor 1A [Htr1aknock-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 alpha-Ca(2+)/calmodulin-dependent protein kinase II (alphaCaMKII) at threonine 286 in the hippocampus of young Htr1a(KO) mice under anxiety-provoking conditions. Increases in alphaCaMKII 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 alphaCaMKII phosphorylation were found in adult knock-out mice, suggesting a transient role of alphaCaMKII as a downstream target of the receptor. Finally, the anxiety phenotype was abolished when knock-out mice were crossed to mice in which alphaCaMKII phosphorylation was compromised by the heterozygous mutation of threonine 286 into alanine. These findings suggest that modulation of alphaCaMKII function by serotonin during a restricted postnatal period contributes to the developmental programming of anxiety-related behavior.
Mouse Biology Unit, European Molecular Biology Laboratory, 00015 Monterotondo, Italy.
Luisa
L
Lo Iacono
Cornelius
C
Gross
D000199:Actins / Q000378:metabolism; D000409:Alanine / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics*; D001522:Behavior, Animal; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D051528:Guanylate Kinases; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D007036:Hypothermia, Induced; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D044282:Receptor, Serotonin, 5-HT1A / Q000172:deficiency*; D012702:Serotonin Antagonists / Q000627:therapeutic use; D013574:Synaptosomes / Q000378:metabolism; D013912:Threonine / Q000235:genetics / Q000378:metabolism
D000199:Actins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D013912:Threonine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051528:Guanylate Kinases; D000409:Alanine