Figure 7.

TARPγ-8 function is required for CaMKIIβ-mediated enhancement of GluA1 expression in the PSD and behavioral response to chronic stress

(A) Experimental paradigm for AAV injection, stress exposure, and behavioral testing. BALB mice were injected with AAV- CaMKIIβ-CA and subjected to 5-day exposure to subchronic and mild social defeat stress (smSDS).

(B) Immunoblot estimation of phosphorylated TARPγ-8 (pTARPγ-8) and total TARPγ-8 levels in the vCA1 of BALB mice injected with AAV-CaMKIIβ-CA or AAV-GFP. n = 8 mice per group.

(C) Experimental paradigm for AAV injection, stress exposure, and behavioral testing. B6 mice were injected with AAV-CaMKIIβ-DN and subjected to 5-day smSDS exposure.

(D) Immunoblot estimation of pTARPγ-8 and total TARPγ-8 levels in the vCA1 of B6 mice injected with AAV-CaMKIIβ-DN or AAV-GFP. n = 8 mice per group.

(E) Experimental paradigm for AAV injection, stress exposure, drug treatment, and behavioral testing.

(F–H) Immunoblot estimation of the PSD (G) and synaptosomal (H) GluA1 levels in the vCA1 of BALB mice exposed to smSDS. JNJ55511118 or vehicle was infused into the vCA1 region during the 5-day smSDS session. n = 8 mice per group.

(I) Increased time in the interaction zone after CaMKIIβ-CA overexpression is disrupted by treatment with JNJ55511118. n = 14–15 mice per group.

(J) Experimental paradigm for AAV injection, stress exposure, drug treatment, and behavioral testing.

(K–M) Immunoblot estimation of the PSD (L) and synaptosomal (M) GluA1 levels in the vCA1 of smSDS-exposed B6 mice. Mice were injected with AAV-CaMKIIβ-DN or AAV-GFP and AAV-TARPγ-8^D/D-T2A-mCherry or AAV-mCherry. n = 10 mice per group.

(N) Decreased time in the interaction zone after CaMKIIβ-DN overexpression is prevented by TARPγ-8 activation. n = 14–15 mice per group.

(O) Proposed model of stress-induced depression based on vCA1 CaMKIIβ: In stress-resilient animals, the Camk2b transcript is normal but CaMKIIβ activity is enhanced following stress episodes. Increased CaMKIIβ activity stimulates the phosphorylation of TARPγ-8, which promotes GluA1 expression in synaptic sites, leading to stress adaptation. In stress-susceptible animals, the Camk2b transcript and CaMKIIβ function are downregulated, leading to reduced TARPγ-8 activity and GluA1 insertion. As a result, vCA1 dysfunction may cause depression-like behavioral alterations such as social impairment and anhedonia.

One-way ANOVA followed by a Tukey's post hoc test (in I and N) and two-tailed Student's t-test (in B, D, G, H, L, and M) were used for statistical analyses. ∗p < 0.05. Bar graphs show mean ± SEM. Complete statistical summaries are provided in Table S2.