CaMKIIα knockdown decreases anxiety in the open field and low serotonin-induced upregulation of GluA1 in the basolateral amygdala

• Low serotonin (5-HT) increased anxiety and glutamate receptor (GluA1) expression.
• Depletion of 5-HT in the basolateral amygdala (BLA) increased CaMKII activation.
• CaMKII activation correlated with anxiety and GluA1 expression.
• Knockdown of CaMKII in the BLA attenuated anxiety and decreased GluA1 expression.

Hyperactivation of the amygdala is implicated in anxiety and mood disorders, but the precise underlying mechanisms are unclear. We previously reported that depletion of serotonin (5-hydroxytryptamine, 5-HT) in the basolateral nucleus of the amygdala (BLA) using the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) potentiated learned fear and increased glutamate receptor (Glu) expression in BLA. Here we investigated the hypothesis that CaMKII facilitates anxiety-like behavior and increased Glu/AMPA receptor subunit A1 (GluA1) expression following depletion of 5-HT in the BLA. Infusion of 5,7-DHT into the BLA resulted in anxiety-like behavior in the open field test (OFT) and increased the phosphorylation of CaMKIIα (Thr-286) in the BLA. Knockdown of the CaMKIIα subunit using adeno-associated virus (AAV)-delivered shRNAi concomitantly attenuated anxiety-like behavior in the OFT and decreased GluA1 expression in the BLA. Our results suggest that the CaMKII signaling plays a key role in low 5-HT-induced anxiety and mood disturbances, potentially through regulation of GluA1 expression in the BLA.

Figure optionsDownload high-quality image (204 K)Download as PowerPoint slideMolecular model of the putative relationship between 5-HT depletion, the CaMKII signaling pathway, and GluA expression in the BLA. Decreased 5-HT removes the tonic inhibition in the BLA, increasing glutamate signaling. The sustained increase in neurotransmission elevates postsynaptic intracellular calcium and activates CaMKII. Activation of CaMKII then increases transcription and membrane expression of GluAs.